EA038613B1 - Blended formulations - Google Patents

Abstract

The invention relates to a formulation comprising blends of formulations (or colloidal dispersions) and its topical application. The formulation comprises at least two different types of colloidal dispersion comprising deformable colloidal particles, wherein the deformable colloidal particles comprise a non-ionic surfactant and/or a phospholipid. The deformable colloidal particles of the invention may comprise an agent of interest (AOI) or may be free of an AOI. The formulation may comprise an AOI that is not associated with the deformable colloidal particles. The invention also includes kits comprising the formulation of the invention and the use of the formulation in medicine, skin care and cosmetics.

Description

The present invention relates to a composition containing mixtures of compositions (or colloidal dispersions), and to its topical use. The composition contains at least two different types of colloidal dispersions containing deformable colloidal particles, where deformable colloidal particles contain a non-ionic surfactant and / or phospholipid. Deformable colloidal particles according to the present invention may contain an agent of interest (CA), or may not contain CA. The composition may contain CA, which is not associated with deformable colloidal particles. The present invention also provides kits containing the composition of the present invention and the use of the composition in medicine, skin care and cosmetics.

Examples of colloidal dispersions containing colloidal particles containing a non-ionic surfactant and a phospholipid, where the colloidal dispersions do not contain any pharmaceutically active CA, are known from WO 2010/140061, which describes the use of drug-free (void) vesicles for treating deep tissue pain associated with osteoarthritis.

Additional examples of colloidal dispersions containing colloidal particles containing a nonionic surfactant and a phospholipid containing CA are known from WO 2015/014965. WO 2015/014965 describes the use of said vesicles for the local administration of therapeutic, metabolic or structural CA, which is attached to the lipid and / or surface-active component of the vesicles, and thus the bulk of the CA is located outside the vesicles.

None of these documents describe or mention a composition containing combinations or mixtures of different types of colloidal dispersions, and furthermore, they do not describe or mention a composition containing CA that is not associated with colloidal particles of colloidal dispersions.

The indication of any references to sources in this section of the present invention does not mean that said reference is included in the prior art of the present invention.

The content of the aforementioned publications is hereby incorporated into this application in its entirety by reference.

Colloidal dispersions containing colloidal particles have previously been used to treat skin conditions or as a cosmetic to improve the appearance of the skin. These colloidal dispersions were also used to introduce CA into the body for the same purposes. In some cases, as described, for example, in WO 2013/171131, the active agent is applied directly to the skin and a drug-free colloidal dispersion is applied over the active agent to push it through the skin, presumably under the influence of hydrophilic forces. In other cases, as described, for example, in WO 2011/022707, non-drug vesicles are used to treat atopic eczema, dyshidrotic eczema of the hands, plaque psoriasis, seborrheic eczema and acne vulgaris. In WO 2015/014965 examples of colloidal dispersions containing CA are used for various purposes. For example, vesicles containing antioxidants or vitamins are used to improve skin repair ability, and colloidal dispersions containing vitamin D can be used as an additive to sunscreen to prevent vitamin D deficiency.

However, these drug-free (i.e., CA-free) colloidal dispersions and CA-containing colloidal dispersions are used separately. Thus, if a consumer needs multiple formulations to act, for example, if it is necessary to reduce the number of bacteria that cause acne, as well as to reduce the production of sebum, it may first be necessary to apply a colloidal dispersion containing zinc to kill the bacteria, dry it and then apply it not. a drug-containing colloidal dispersion to remove excess sebum. This causes a number of difficulties for the consumer. For example, if the active agent is applied directly to the skin and then a colloidal dispersion is applied, there is little or no dose control when the active agent is administered. An indefinite amount of active agent is applied to the skin and then an indefinite amount of colloidal dispersion. The consumer cannot know exactly how much of the active agent is delivered through the skin. In addition, applying the active agent directly to the skin means that it is applied at a high concentration, which increases the likelihood of adverse skin reactions occurring. In addition, if two CAs are applied in the absence of colloidal dispersions, they can react with each other, so the consumer cannot know exactly what combination of starting and reaction products he is getting. It is important to note that the need for separate application of two or more colloidal dispersions takes a lot of time from the consumer, since drying of each colloidal dispersion can take up to 10 minutes.

The present invention overcomes these problems by combining different colloidal dispersions in one convenient formulation for application, where the interaction of the individual CAs does not occur. The colloidal nature of these mixed dispersions ensures that each dispersion is separate and stable prior to application to the skin. Thus, colloidal dispersions can have separate functions and can be administered together in one formulation in one simple application step. This allows the consumer to save time, provides more accurate dosing (the ratio of CA to colloidal particles in terms of grams is constant) and reduces unwanted reactions on the skin.

Accordingly, in a first aspect, the present invention provides a composition comprising a first colloidal dispersion and a second colloidal dispersion, wherein each colloidal dispersion comprises deformable colloidal particles containing a surfactant and optionally a phospholipid, and one or more deformable colloidal particles in the first colloidal dispersion contain the first target agent (CA).

By one or more is meant from about 1 to about 5%, from about 5 to about 10%, from about 10 to about 20%, from about 20 to about 40%, from about 40 to about 60%, from about 60 to about 80%, about 80 to about 85%, about 85 to about 90%, about 90 to about 92%, up to about 94%, up to about 96%, up to about 97%, up to about

98%, up to about 99%, or up to about 100%, or from about 98 to about 100%.

If colloidal dispersions contain at least one or more deformable colloidal particles containing CA, then not all deformable colloidal particles may contain CA. CA is added in the preparation of colloidal dispersions, and it can attach to some deformable colloidal particles, but not others. For example, the amount of added CA may be insufficient for CA to attach to each colloidal particle.

One or more deformable colloidal particles in the second colloidal dispersion may also contain CA, in which case the CA in the first colloidal dispersion and CA in the second colloidal dispersion are different.

One or more deformable colloidal particles in the first colloidal dispersion and / or one or more deformable colloidal particles in the second colloidal dispersion contain one or more additional CAs, where each CA is different.

The composition may contain one or more additional colloidal dispersions containing deformable colloidal particles containing a surfactant and, optionally, a phospholipid, wherein one or more particles in each dispersion may contain additional CA, first CA, second CA, and each additional CA is different. The composition may include additional colloidal dispersions containing deformable colloidal particles containing a surfactant and / or phospholipid without CA.

Deformable colloidal particles in one colloidal dispersion can contain more than one type of CA. For example, deformable colloidal particles in the first colloidal dispersion may contain a first CA and a second CA, where the first CA and the second CA are different. Deformable colloidal particles in one colloidal dispersion can contain two, three, four, five or more different types of CA. All different types of CA can be attached (attached or linked) to a colloidal particle in dispersion in various combinations.

The composition may contain two or more colloidal dispersions containing colloidal particles, where the colloidal particles in each dispersion contain the same amount or different amounts of different types of CA. For example, the composition may contain a first colloidal dispersion containing colloidal particles to which two different types of CA are attached (linked or attached), and a second colloidal dispersion containing colloidal particles to which two different types of CA are also attached.

Alternatively, the composition may comprise a first colloidal dispersion containing colloidal particles to which two different types of CA are attached, and a second colloidal dispersion containing colloidal particles to which three different types of CA are attached. The composition may contain two or more colloidal dispersions containing colloidal particles to which no CAs are attached or to which one, two, three, four, five or more different CA types are attached.

Colloidal dispersions are also known as Sequessome ™, Transfersome ™ or Tethersome intermediates.

The deformable colloidal particles of the present invention can be vesicles. CA can be incorporated into the vesicle membrane. CA may be associated with a component of the vesicle membrane. More specifically, CA can be associated with the surface-active component of the vesicle membrane or with the lipid component of the vesicle membrane. CA can be associated with both the surface-active component and the lipid component of the vesicle membrane. The bond can be a covalent bond.

CA can be associated with a component of the particle in such a way that at least part of the CA is on the outer surface of the particle outside the particle membrane. Preferably, the component to which the CA is bound is a lipid and / or surface active component. At least part means that at least 5, 10 or 20%, usually 40% or more than 50% of each CA molecule (if we consider the size or volume of the molecule) is outside the particle membrane. Preferably, the majority of the CA, more preferably all of the CA molecule is outside the particle. CA

- 2 038613 can be covalently linked to the component in such a way that it is entirely on the outer surface of the particle.

The location of the CA outside the particle means that these CAs are facing outward.

In one method for preparing particles in which a surface active or lipid component that is bound or otherwise attached to CA is mixed with unmodified components, the orientation of the modified molecule cannot be controlled. Thus, approximately 50% of the molecules to which the CA is attached are in the wrong orientation, which means that part of the CA is inside the particle cavity.

In another process for the preparation of particles, in which a surface active or lipid component that is bound or otherwise attached to CA is mixed with the particles already prepared, the surfactant or lipid component attached to CA is preferably combined with the existing particle in such a way that CA, as a rule, remains outside the particle. Thus, approximately from 0 to 10% of the molecules to which the CA is attached have the wrong orientation, which means that if CA is present in the particle cavity, its content is low. In modified molecules that have the correct orientation, in which CA is outside the particle, at least 50% of the CA molecule, as such, in terms of physical size / volume, is outside the vesicle membrane. The production method can reduce the proportion of CA located outside the particle, i. E. external concentration of CA can be from 1 to 10% (including 2, 3, 4, 5, 6, 7, 8 or 9%), from 10 to 50%, from 15 to 45%, from 20 to 40% or from 25 up to 30% (w / v) of the total amount of CA in the composition. External concentration is understood to mean the concentration of CA that are available for release and / or exhibit therapeutic activity after the particles have passed through the skin.

A particle in the composition may contain one CA or a set of CA associated with its outer surface. If a set of target audiences is connected, then target audiences can be the same, i.e. homogeneous, or CA can be different, i.e. heterogeneous.

The CA to be bound can be attached via covalent or other bonds directly to the phospholipid or surface-active component of the particle or to the lipid component of the particle. The use of a linker or bridging group that is attached via covalent or other bonds to a fatty acid, surfactant or lipid component, and to CA may be preferred. In one example, if an inorganic CA (e.g., a metal, metal salt, or metal oxide) is to be added, a conjugate of an additional linker, e.g., a metal chelating agent (such as EDTA), stearic acid, or palmitic acid with component of the particle. In another example, it may be desirable to use a longer molecule, for example a polymer (such as polyethylene glycol; PEG), to increase the efficiency of the binding process and / or the efficiency of the coupled CA. These linkers / long bridging molecules can be especially effective when it is required to keep CA at a distance from the particles to prevent direct interaction with the membrane. This can happen if the CA is highly lipophilic.

CA can be associated (or attached or attached) to the surfactant component of the colloidal particle. Binding to a surfactant can occur directly on the surface of the surfactant through an ester bond if the molecule contains a hydroxyl group. An alternative method of bonding is the substitution of an atom or functional group in the surfactant (for example, in the case of Tween, a polyethylene glycol polymer) with CA. In the third method, direct coupling to the fatty acid is carried out, optionally via an ester linkage. If CA is an inorganic molecule, then a conjugate of an additional linker molecule with a vesicle component may first be prepared, for example a conjugate with a metal chelating agent such as EDTA in the case of a metal salt. If the CA must be kept at some distance from the vesicle to maximize its effectiveness (for example, to influence the active site of an additional ingredient, which is an enzyme), then a linker molecule, for example, a polymer chain (for example, polyethylene glycol), can be associated with a colloidal component. particles and with CA.

CA can be attached (bound or attached) to the lipid component of the colloidal particle. Binding to a lipid can be achieved through any of the hydroxyl groups of glycerol through an ester bond, for example, by cleaving a fatty acid and replacing it with CA. Alternatively, the attachment method may involve replacing the phosphatidyl moiety, such that the final molecule contains two fatty acid chains together with attached CA. The modified lipid is incorporated into the aliphatic region as usual, and due to free rotation relative to the glycerol matrix, the attached CA can be located outside the vesicle. The amide bond can be used as a more stable alternative if the CA must be attached to a deformable colloidal particle for an extended period of time. This may be necessary, for example, if the target of CA is deep tissue, such as the reticular layer of the dermis, rather than the upper layers of the skin (such as the epidermis). A combination of less stable and more stable bonds (for example, ester and amide bonds, respectively) can be used to

- 3 038613 ensuring the gradual release of CA.

The method of forming bonds with any component can include the formation of hydrolysable or non-hydrolysable bonds. If there is a need for CA to be released immediately after getting inside the skin or under the skin, then this bond must be hydrolysable. If there is a need for the bound CA to remain attached to the vesicle after entering the skin or under the skin, then the bond must be non-hydrolysable.

CA can be covalently linked or conjugated to a membrane component; the bond can be hydrophilic, or hydrophobic, or hydrostatic; the bond can be a hydrogen bond or an ionic bond.

The terms linking, attachment, and attachment, which are used interchangeably herein, include all linkages noted above.

CA can be selected from the group consisting of element, peptide, protein, micronutrient, ion, inorganic salt, small molecule, amino acid, carbohydrate, lipid, macromolecule, or macrocyclic molecule.

CA can be a structural protein of the skin (such as elastin or collagen), a therapeutic protein, a macromolecule containing porphyrin or chromophore, a vitamin (such as vitamin C, D, or E), titanium dioxide, zinc, zinc oxide, zinc stearate, melanin, or analogue of melanin. CA can be a peptide or a synthetic organic chemical such as an anti-inflammatory drug such as NSAIDs.

The first CA, the second CA and / or each additional CA can be selected from the group consisting of zinc, ascorbate (vitamin C), vitamin D, tocopherol (vitamin E), tetrapeptide, tripeptide, salicylic acid, or menthol. In particular, CA can be selected from the group consisting of zinc stearate, palmitoyl ascorbate (or palmitoyl ascorbic acid (PAA)), palmitoyl tripeptide, palmitoyl tetrapeptide, salicylic acid, or menthol. More specifically, CA may be selected from the group consisting of zinc stearate, palmitoyl ascorbate, palmitoyl tripeptide-1, palmitoyl tetrapeptide-7, tocopherol linoleate, salicylic acid, or menthol. Salicylic acid can be myristyl salicylate or tridecyl salicylate.

Peptides such as tetrapeptide-7 or tripeptide-1 can be associated with a fatty acid or a surface active component of the vesicle membrane. Tetrapeptide-7 can be effective in fighting inflammation and stimulating skin repair through collagen production. This means that it is especially suitable for skin care and anti-aging products. Tripeptide-1 has a similar effect. Efficient delivery through the outer layer of the skin can provide enhanced action at a reduced level / concentration, thereby minimizing potential side effects caused by suppression of interleukins.

Vitamin C (water-soluble ascorbate) is a cofactor in many enzymatic reactions, including several collagen synthesis reactions. These reactions are important in wound healing and in preventing capillary bleeding. Thus, the present invention includes the formation of associates of ascorbate with a vesicle component for incorporation in skin care and sunscreen formulations to mitigate collagen damage and for inclusion in wound care products.

Vitamin E has important antioxidant properties and may reduce the signs of aging and sun damage. Linoleate is an ester of linoleic acid, an omega-6 fatty acid that has anti-inflammatory and moisturizing properties. Tocopheryl linoleate combines the properties of vitamin E and linoleate to reduce the signs of aging and moisturize the skin. Thus, it is possible to obtain associates of vitamin E or tocopheryl linoleate with a vesicle component for incorporation into anti-aging and skin regeneration products.

Vitamin D can be included in the compositions of the present invention by forming associates with the vesicle component.

In mammalian skin, vitamin D3 is produced by exposure of its precursor, 7-dehydrocholesterol, to UV radiation, thus producing approximately 90% of vitamin D in the body. Sunscreens absorb ultraviolet light and prevent its effects on the skin.

If the formulation contains vitamin D ₃ (this does not mean that the formulation also does not contain vitamin C and / or E), then the formulation can be included in a sunscreen product, sunscreen product, after-sun care product or other skin care or cosmetic product. a product to replenish low vitamin D levels. Lowered vitamin D levels can be caused by low light conditions or the use of sunscreen products that can prevent the body from producing vitamin D.

Zinc is an antioxidant and antimicrobial agent. It is beneficial to the immune system and helps to slow down aging, accelerate wound healing, kill microorganisms and bacteria, and downregulation of sebum production in the sebaceous glands. In on

- 4,038613 It is currently used in a variety of topical skin preparations such as sunscreens to protect against burns and anti-dandruff shampoos to kill dandruff-causing fungi. It is also used to treat acne. According to the present invention, zinc is attached to vesicle components for incorporation into skin care products, which, for example, can be applied to reddened dry itchy skin, to reddened irritated flaky skin, or to acne-prone skin to improve its condition.

Salicylic acid is a beta-hydroxy acid (BHA) having the formula SbH ₄ (OH) COOH. It can be obtained from willow bark. Salicylic acid is an important active metabolite of aspirin (acetylsalicylic acid), which in part acts as a prodrug of salicylic acid. It is widely used as a pain reliever, it also has anti-inflammatory, antipyretic, antidiabetic, bactericidal and antiseptic effects. As a result, salicylic acid is an important ingredient in pain relievers, topical anti-acne products, topical irritating products, skin care products for treating conditions such as psoriasis, corns, ichthyosis and warts, dandruff shampoos, tanning products, and sun protection , mouthwash and toothpaste. It can also be used to prevent or treat uneven skin tone caused by, for example, black age spots and liver spots. Salicylic acid can be used in the form of myristyl salicylate or tridecyl salicylate.

The aggregate of CA can be bound to a lipid or surface-active component for placement on the outer surface of the particle, thus, after passing through the skin, they are retained on the surface of the particle. Examples include antioxidants; vitamins; inorganic compounds such as TiO2 and ZnO; porphyrin molecules for use in photodynamic therapy, or any CAs mentioned above.

Obviously, other CAs can be attached to the deformable colloidal particles of the present invention to treat a variety of diseases.

The composition may or may not contain any known therapeutic agent other than particle bound CA. A formulation containing CA may or may not contain any additional CA. Additional CA may or may not be associated with colloidal particles.

CA can be a target agent, such as a cosmetic, that has no biological or pharmacological effect, or can be a biologically active or pharmaceutically active agent.

Colloidal dispersions in the composition contain at least two phases; a dispersed phase containing suspended deformable colloidal particles, and a continuous phase containing a suspending medium (or matrix). The composition may contain two, three, four or more dispersed phases. The dispersed phases can contain different types of colloidal particles, such as different types of vesicles, for example Sequessome ™, Transfersome ™, Tethersome, micelles and liposomes. The composition may contain one or more dispersed phases containing deformable colloidal particles such as Sequessome ™, Transfersome ™ or Tethersome, and optionally one or more dispersed phases containing non-deformable colloidal particles such as micelles and / or non-deformable vesicles such as liposomes ... The composition may contain two or more types of deformable colloidal particles.

Typically, the term Transfersome ™ is used to describe a deformable vesicle containing a phospholipid and a surfactant associated with CA, in particular where CA is retained within the vesicle cavity or is bound within the vesicle membrane. As used herein, the term Sequessome ™ is used in its usual sense to describe a deformable vesicle containing a phospholipid and a surfactant. If the CA is attached to the vesicle in such a way that it is retained outside of the outer surface of the membrane, then the vesicle (or Sequessome ™) can be called a Tethersome.

CA can be kept in a continuous phase. Preferably, said continuous phase comprises a non-lipid phase, most preferably an aqueous phase.

Alternatively, CA may be present in the second dispersed phase (where the first dispersed phase contains deformable colloidal particles). For example, CA can be associated with non-deformable colloidal particles, such as micelles, or with non-deformable vesicles, such as liposomes.

The composition can be a liquid, cream, lotion, ointment, gel, solution, spray, varnish, or film-forming solution. Preferably, the composition can be a gel.

As noted above, the composition according to the first aspect of the invention may contain CA that is not associated with deformable colloidal particles in the composition.

When used in the present description, the phrase not associated means that CA is not attached to the deformable colloidal particle or is not inside it. In particular, the CA is not attached,

- 5 038613 is not bound or otherwise attached to a deformable colloidal particle, is not located within the structure of a deformable colloidal particle, including a lipid bilayer or fluid enclosed within a lipid bilayer, is not encapsulated within a deformable colloidal particle or otherwise directly not associated with a deformable colloidal particle. On the contrary, CA is in a composition phase that differs from deformable colloidal particles. For example, CA can be contained in the continuous phase of the composition, for example, it can be dissolved in the continuous phase. Alternatively, CA can be contained in a different dispersed phase of the composition, for example, as insoluble aggregates or associates with non-deformable colloidal particles such as micelles and non-deformable vesicles such as liposomes. Preferably, the CA is in a form in which it cannot normally pass through the skin without the use of deformable colloidal particles.

The composition according to the present invention is multiphase due to the fact that, as indicated above, it contains at least two phases: a dispersed phase containing suspended deformable colloidal particles and a continuous phase containing a suspending medium. In a multiphase system, there are individual particles, clusters or formations dispersed or suspended in a medium or matrix. Each phase is a separate solid or liquid component with a detectable interface. In colloidal systems, the particle size in each phase is very small so that they can be observed with the naked eye. However, the multiphase nature of the system can be demonstrated by applying a narrow beam of light, the Tyndall beam, which can be seen as its passage through the solution by scattering light at the phase boundary (s). It is impossible to see the passage of the specified light beam through a single-phase solution.

The composition according to the present invention may contain more than two phases. For example, the composition may contain two, three, four, or more dispersed phases in addition to the continuous phase. These two dispersed phases may contain deformable colloidal particles that direct the CA through the skin. The third dispersed phase may contain CA, for example, in the form of insoluble aggregates or associates with non-deformable colloidal particles. Other dispersed phases may also be provided containing additional deformable and / or non-deformable colloidal particles.

The composition may contain two or more colloidal dispersions.

Preferably, the continuous phase contains a non-lipid phase. The continuous phase can be selected depending on the type of CA and the need to dissolve the CA in the continuous phase or provide it in the form of a dispersed phase. Preferably, the continuous phase is an aqueous phase.

Although CAs can be provided in a separate phase other than deformable colloidal particles, under certain conditions well known to those skilled in the art, some CAs can be enclosed in a membrane or liquid core of deformable colloidal particles. Preferably, only a negligible or negligible amount of CA, provided in a separate phase other than the deformable colloidal particles, is enclosed in the deformable colloidal particles, while a significant amount of CA remains in the separate phase. Preferably about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, about 0.5% or less, about 0.1% or less, or about 0% CA is enclosed in deformable colloidal particles. Preferably at least about 95.0%, at least about 96.0%, at least about 97.0%, at least about 98%, at least about 99.0%, at least about 99, 5%, at least about 99.9%, or about 100% of the CA in the composition are in a separate phase other than the deformable colloidal particles.

The composition according to the first aspect of the present invention may contain two significant assemblies of one CA: a first assembly that is not associated with deformable colloidal particles, and a second assembly that is associated with deformable colloidal particles, for example, attached to deformable colloidal particles. In these embodiments, the first set of CAs can penetrate deeper into the skin as compared to the second set of CAs, which provides an effect on tissues at different depths.

If the composition according to the first aspect of the present invention contains these two sets of one CA, then the relative content of the first set and the second set is selected in accordance with the different purposes for which each of the sets is intended. Preferably, the ratio of the first population to the second population is in the range 20:80 to 80:20, 30:70 to 70:30, 40:60 to 60:40, or about 50:50.

As used herein, the phrase target agent or CA includes, but is not limited to, biologically active or pharmaceutically active agents. A biologically or pharmaceutically active agent is defined herein as an agent that has pharmacological, metabolic, or immunological activity. These agents may include chick-pea-6 038613 receutical or pharmaceutical agents. Where appropriate, the CA should preferably be approved by the regulatory body.

CA can be an antiseptic, antibiotic, anesthetic, pain reliever, skin whitening agent, antihistamine, steroid, anti-inflammatory agent, antiviral agent, sunscreen, moisturizer, nicotine, antifungal, antimicrobial, nutraceutical, essential oil, or hormone.

Preferably CA, which is not associated with deformable colloidal particles, is selected from the group including, but not limited to, chlorhexidine or a salt thereof, capsaicin, salicylic acid or a salt or ester thereof, glucosamine or a salt thereof, glucosamine amide or a salt thereof, chondroitin or its salt, caffeine or tocopherol.

If the CAs listed above are added to the organic phase of the composition during preparation (i.e., before the formation of deformable colloidal particles), then some CA may be contained inside the cavity of colloidal particles, and some CA may be contained in the continuous phase of the composition (i.e. do not associate with colloidal particles). The distribution of CA may depend on the specific nature of the CA included in the composition.

Chlorhexidine, N, N1,6-hexanediyl-bis- [N '- (4-chlorophenyl) (imidodicarbonimide acid)] diamide, is a cationic polybiguanide (bisbiguanide). It is an antimicrobial compound that is effective against a wide range of gram-positive and gram-negative bacteria and some fungi and viruses. It is widely used in topical disinfectants, cosmetic and pharmaceutical products including wound dressings and mouthwashes. It is also used to treat acne.

Chlorhexidine is often used as a salt. Preferably, the chlorhexidine salt is selected from the group consisting of chlorhexidine dihydrochloride, chlorhexidine diacetate, chlorhexidine gluconate and chlorhexidine digluconate. Most preferably, the composition contains chlorhexidine gluconate.

Chlorhexidine or a salt thereof according to the present invention can be provided as a 10% solution, a 20% solution, a 30%, 40% solution, or a 50% solution. Preferably, chlorhexidine or a salt thereof can be provided as a 20% solution. The composition according to the present invention may contain from 0.1 to 2.5 wt.%, More preferably from 0.5 to 2.0 wt.%, Most preferably 1.5 wt.% 10% solution, 20% solution, 30% solution, 40% solution or 50% solution. Preferably, the composition according to the present invention may contain from 0.1 to 2.5 wt%, more preferably from 0.5 to 2.0 wt%, most preferably 1.5 wt% of a 20% solution. Thus, the composition may contain from 0.02 to 0.1 wt%, from 0.1 to 0.2 wt%, from 0.2 to 0.3 wt%, from 0.3 to 0.4 wt%, 0.4 to 0.5 wt%, 0.5 to 1.1 wt%, or 1.1 to 1.25 wt% chlorhexidine. Preferably, the compositions according to the present invention contain chlorhexidine or a salt thereof at a concentration below the critical micelle concentration.

Chlorhexidine or its salt can be contained in the composition in the form of insoluble aggregates or micelles. If CA, not associated with deformable colloidal particles, contains chlorhexidine or a salt thereof, the continuous phase is preferably aqueous.

Capsaicin, 8-methyl-N-vanilyl-6-nonenamide, is a capsaicinoid produced as a secondary metabolite by fruits of the Capsicum genus, including chili peppers. It is believed to deter mammals from eating these plants, and also to act as an antifungal agent. In medicine, capsaicin is used as an analgesic agent, in particular for the temporary relief of pain associated with arthritis, headache, pain in sprains and dislocations, fibromyalgia and neuralgia. It is also used to relieve itching associated with conditions such as psoriasis.

The compositions according to the present invention may contain from 0.01 to 0.1% capsaicin, more preferably from 0.01 to 0.05%, most preferably about 0.025%.

Capsaicin can be dissolved in the continuous phase if the continuous phase contains a suitable solvent such as diethyl ether, benzene and / or alkane.

Preferably, the capsaicin is contained in the composition as insoluble aggregates or associates with non-deformable colloidal particles such as liposomes containing one or more phospholipids. Preferably, the capsaicin is bound to the liposome membrane. Under these conditions, the continuous phase is preferably aqueous.

As noted above, salicylic acid is widely used as an analgesic agent, and it also has anti-inflammatory, antipyretic, antidiabetic, bactericidal and antiseptic effects.

Salicylic acid can be used for the above applications in the form of a salt or ester. Salicylic acid salts include calcium salicylate, magnesium salicylate, MEA salicylate, potassium salicylate, sodium salicylate, and TEA salicylate. Salicylic acid esters include butyloxyl salicylate, C12-15 alkyl salicylate, sapryloyl salicylic acid, hexyldecyl licylate, isocetyl salicylate, isodecyl salicylate, ethylhexyl salicylate, methyl salicylate, and myristyl salicylate, and myristyl salicylate.

Preferably, the composition according to the first aspect of the present invention comprises a salicylic acid ester, most preferably myristyl salicylate or tridecyl salicylate.

The composition according to the present invention may contain salicylic acid, or a salt or ester thereof, in concentrations suitable for the intended use and within the limits of regulatory restrictions.

Salicylic acid and its salts and esters are water-soluble, and thus, if the continuous phase is aqueous, salicylic acid or a salt or ester thereof can be dissolved in the continuous phase. At least some of the salicylic acid or its salt or ester may also be contained in the membrane of the deformable colloidal particles according to the present invention and / or in the membrane of one or more non-deformable colloidal particles also contained in the composition. The compositions of the present invention preferably contain from about 0.05 to 2.5 wt% salicylic acid or a salt or ester thereof.

In solution, chlorhexidine and its salts, capsaicin and salicylic acid and its esters and salts can form micelles, vesicles or insoluble aggregates.

Glucosamine, or (3R, 4R, 5S) -3-amino-6- (hydroxymethyl) oxane-2,4,5-mriol, is an amino sugar and is the main precursor in the biochemical synthesis of glycosylated proteins and lipids. It is often used as a dietary supplement, particularly in the treatment of osteoarthritis.

Glucosamine can be used as an amide such as N-acetylglucosamine.

The compositions of the present invention may contain glucosamine salts or glucosamine amides such as glucosamine sulfate, glucosamine hydrochloride and N-acetylglucosamine sulfate.

The compositions of the present invention may contain from about 0.01 to 1.0 wt% glucosamine, glucosamine amides or salts thereof, more preferably from about 0.05 to 0.5 wt%, more preferably from about 0.1 to 0 , 3 wt.%, Most preferably about 0.2 wt.%.

Glucosamine, glucosamine amides and their salts are water soluble. Thus, if the continuous phase of the composition is aqueous, then these agents can be dissolved in the continuous phase.

Chondroitin is a glycosaminoglycan (GAG) made up of a chain of alternating sugars, N-acetylgalactosamine and glucuronic acid. It is usually attached to proteins in the proteoglycan. The chondroitin chain can contain more than 100 individual sugars, each of which can be sulfated at different positions in varying amounts.

Chondroitin can be used as a salt such as chondroitin sulfate, chondroitin gluconate, and chondroitin hydrochloride. Chondroitin sulfate is an essential component of cartilage and has begun to be widely used as a dietary supplement in the treatment of osteoarthritis.

The compositions according to the present invention may contain from about 0.01 to 1.0 wt.% Chondroitin or its salts, more preferably from about 0.05 to 0.5 wt.%, More preferably from about 0.1 to 0.3 wt. .%, most preferably about 0.2 wt.%.

Chondroitin and its salts such as chondroitin sulfate are water soluble. Thus, if the continuous phase of the composition is aqueous, then these agents can be dissolved in the continuous phase.

Caffeine, or 1,3,7-trimethylpurine-2,6-dione, is a methylxanthine alkaloid that is commonly found in the seeds, nuts, or leaves of various plants found in South America or East Asia. Despite its widespread use as a central nervous system stimulant, caffeine is also a powerful antioxidant and anti-inflammatory agent that can be applied topically to reduce wrinkles, puffiness around the eyes, and dark circles under the eyes. It can also be used to prevent sun damage to the skin.

The compositions of the present invention may contain from about 0.001 to 1.0 wt% caffeine, more preferably from about 0.01 to 0.5 wt%, more preferably from about 0.02 to 0.1 wt%, more preferably 0.02 to 0.08 wt%, most preferably 0.05 wt%.

Caffeine is soluble in water. Thus, if the continuous phase of the composition is aqueous, then the caffeine can be dissolved in the continuous phase. At least some of the caffeine may also be contained in the membrane of the deformable colloidal particles according to the present invention and / or one or more non-deformable colloidal particles also contained in the composition.

The compositions according to the present invention may contain more than one CA that is not associated with deformable colloidal particles. For example, a composition according to the present invention may contain glucosamine or a salt thereof and / or glucosamine amide or a salt thereof in combination with chondroitin or a salt thereof. For example, the composition of the present invention may contain glucosamine hydrochloride and / or N-acetylglucosamine sulfate in combination with chondroitin sulfate.

Tocopherols are a class of organic chemical compounds (more precisely, various methylated phenols), many of which have vitamin E activity. There are four distinct forms of tocopherol: alpha, beta, gamma, and delta. Tocopherols have a number of functions in the body. They have antioxidant and anti-inflammatory effects that help protect cells from the damaging effects of free radicals that can lead to cardiovascular disease and cancer. Tocopherols are involved in normal immune function, gene expression, blood flow, protecting nerve health, and preventing mental degeneration. Tocopherols also play an important role in skin care, protecting the skin from oxidative damage caused by UV radiation and environmental pollution. Topical application of tocopherols can help reduce redness, sunburn, and skin damage, including UV-induced tumor formation. Tocopherols also help protect collagen and elastin-producing cells and provide anti-aging effects. Tocopherols are also effective moisturizers, moisturize the skin and prevent additional water loss, which helps to reduce small and pronounced wrinkles. Tocopherols also reduce wound healing time and can be used to repair damage to the skin and dry skin and to treat skin conditions such as psoriasis and erythema.

Alpha-tocopherol is a form of vitamin E that is preferentially absorbed and stored in the human body.

Tocopherol, preferably alpha-tocopherol, can be contained in the continuous phase of the compositions of the present invention (as free tocopherol).

The compositions according to the present invention may contain from about 0.01 to 1.0% by weight of free tocopherol, such as alpha-tocopherol, more preferably from 0.05 to 0.5% by weight, more preferably from 0.1 to 0, 3 wt%, most preferably about 0.2 wt%. A small amount of free tocopherol can be trapped in the cavities of the deformable colloidal particles, but a significant amount remains in the continuous phase.

Typical compositions according to the first aspect of the present invention containing alphatocopherol in a continuous phase are shown in Example 6 and Example 7.

Derivatives of tocopherols, for example esters such as tocopheryl linoleate, can also be used. These derivatives can be attached to deformable colloidal particles in various compositions according to the present invention, as discussed herein.

The composition may contain at least three colloidal dispersions, at least four colloidal dispersions, or at least five or more colloidal dispersions.

The composition according to the first aspect of the invention contains a surfactant and, optionally, a phospholipid, from which deformable colloidal particles are obtained. The deformable colloidal particles may contain one or more surfactants and be free of phospholipids, one or more phospholipids, and be free of a surfactant or one or more surfactants in combination with one or more phospholipids.

Preferably, said deformable colloidal particles comprise a liquid core, for example an aqueous core, enclosed in a membrane, for example in a two-layer membrane. Suitable bilayer membranes include phospholipid-surfactant bilayer membranes, non-ionic surfactant bilayer membranes, and surfactant-cholesterol bilayer membranes. The term double layer indicates that the membrane is two molecules thick, where each molecule is configured in such a way that its hydrophobic end is oriented inward towards the opposite side of the membrane, and its hydrophilic end is oriented outward towards the surrounding aqueous medium. For example, a bilayer membrane can contain two layers of phosphatidylcholine molecules, where the hydrophobic tails of each molecule are directed towards each other, and the hydrophilic heads of each molecule are directed in different directions relative to each other. Preferably, the composition contains deformable colloidal dispersions containing colloidal particles (i.e. vesicles) containing a lipid bilayer in an aqueous medium. As used herein, the term vesicle includes monolamellar or polylamellar vesicles and micelles. Deformable colloidal particles can also contain niosomes.

Preferably, said deformable colloidal particles have a diameter of from about 50 to 250 nm, from about 60 to 200 nm, from about 70 to 180 nm, from about 80 to 160 nm, preferably from 100 to 150 nm, most preferably about 120 nm.

Deformable colloidal particles according to the present invention are described in WO 2010/140061 and WO 2011/022707.

The composition according to the present invention is particularly suitable for topical administration as it contains ultra-deformable (or flexible) colloidal particles (or microscopic spheres). These flexible colloidal particle forms (Sequessome ™, Transfersome ™ or Tethersome) are vesicles that are bilayer vesicles composed of a surfactant and / or lipid such as a phospholipid. The specific amount of surfactant (if present in the formulation), preferably a nonionic surfactant, allows the lipid membrane to be modified so that the resulting particles are constantly

- 9 038613 were in liquid crystal state. Since the surfactant (if present in the composition) also imparts stability to the membrane, the particles are also ultra-deformable and stable (have a reduced rigidity without destruction).

Colloidal dispersions in the composition form deformable colloidal particles suspended in a suspending medium, for example in an aqueous buffer. The particles are highly hydrophilic, and this property, combined with the ability to ultra-deform, is key for transport through the skin. When the composition of the present invention is applied to the skin and allowed to dry, the motive force of the particles, determined by rehydration, in combination with their deformability, causes the particles to move to areas of high water content above and below the skin's permeability barrier. This ensures their movement through the pores in the skin and the intracellular space. The particular ratio of lipid to surfactant can facilitate transdermal delivery of the particles. As the colloidal particles move through the skin, they push or pull the target audience with them.

While not wishing to be limited to any mechanism of action, it is believed that the compositions of the present invention can form colloidal particles that are deformable. When moving through the pores and intracellular space, deformable colloidal particles carry CA with them, which increases the speed, depth and efficiency of absorption of the specified compound.

The term deformable refers to the ability of colloidal particles to readily change their properties, such as shape, degree of elongation, and surface area to volume ratio. Colloidal particles according to the present invention can be characterized by the ability to adjust their shape and properties to the anisotropic stress caused by the intersection of narrow pores in a semi-permeable barrier such as skin. Sufficient deformation capability implies that the colloidal particle can withstand various unidirectional forces or stresses, such as those caused by pressure, without excessive breakage, which determines a stable colloidal particle.

A barrier in the context of the present invention is a formation with pores passing therethrough that are narrow and have a radius that is at least 25% less than the radius of colloidal particles (considered spherical) before said colloidal particles pass through said pores.

The term narrow when used with respect to pores indicates that the pore radius is significantly, typically at least 25%, less than the radius of the colloidal particle in which the pore penetration test is being performed. The required difference generally increases with decreasing pore size. Using a 25% limit is thus acceptable for diameters> 150 nm, with a difference of> 100% being more appropriate for smaller systems, eg <50 nm diameters.

Preferably, the ability of colloidal particles to deform can be determined by the ability of colloidal particles to pass through a barrier, the pores of which have an average diameter that is at least 25%, at least 30%, at least 35%, at least 40% at least 55%, at least 50%, at least 55%, or at least 60% less than the average particle diameter before passing through the pores. Most preferably, the deformability of the colloidal particles can be determined by the ability of the colloidal particles to pass through a barrier whose pores have an average diameter that is at least 50% less than the average particle diameter before passing through the pores.

The term semi-permeable when used in relation to a barrier indicates that the solution can pass through the holes that pass through the barrier without permeating a suspension of inflexible aggregates (which are large enough for the above definition of narrow pores to apply). Three examples of said inflexible aggregates include conventional lipid vesicles (liposomes) obtained from any commonly used phosphatidylcholine in the lamellar gel phase or also from a mixture of any biological phosphatidylcholine / cholesterol, 1/1 (mol / mol), or also from a comparative large oil droplets, all of which have a specified relative diameter.

The term stable means that colloidal particles do not change their diameter spontaneously or under the influence of mechanical stress associated with transport (for example, when passing through a semipermeable barrier) to an unacceptable level, most often this means a change only to a pharmaceutically acceptable level. A 20-40% change is usually considered acceptable; halving or doubling the diameter of colloidal particles are borderline changes, and a higher change in diameter is generally unacceptable. Alternatively, the change in colloidal particle diameter caused by passage through pores under pressure is conveniently used to assess system stability; the same criteria can then be used for narrow pores, with appropriate amendments. Correction for flow / mixing effects may be required to obtain the correct diameter change. These methods are described in more detail in the publications of the author of the present invention Cevc et. al., Biochim. Bio- 10 038613 phys. Acta 2002; 1564: 21-30.

The passage of colloidal particles through narrow pores of a semipermeable barrier without destruction is thus an indicator of the possibility of their deformation. If the pore radius is half the average radius of the colloidal particles, then the change in shape and the ratio of surface area to volume of colloidal particles must be at least 100% so that they can pass through the barrier without destruction. The ability to easily and reversibly change shape implies a high deformability of colloidal particles and requires significant modification of the surface area to volume ratio. A change in the surface area to volume ratio indicates a) high volumetric compressibility, for example, in the case of compact droplets containing material other than the suspending medium or not miscible with it; b) high permeability through the membrane, for example, in the case of colloidal particles, in which the exchange of fluids between the inner and outer spaces of the particle can take place.

Deformation test methods that can be used to characterize a composition of the present invention are found in WO 2010/140061 and US Patent Applications Nos. 2004/0071767 and 2004/0105881, the contents of each of which are hereby incorporated by reference in their entirety. as if they were fully described in the present description.

If the composition according to the present invention contains two or more colloidal dispersions containing deformable colloidal particles containing CA, and in some cases CA not associated with colloidal particles, then the composition can provide action in different layers of the skin. Colloidal particles can efficiently pass through the skin and deliver CA to the deeper layers of the dermis, while the CA agent can remain on the skin surface or in the upper layers. This makes it possible to target each area of the skin in the most effective way to treat a specific condition.

According to a second aspect, the present invention provides a composition comprising a first colloidal dispersion and a second colloidal dispersion, wherein each colloidal dispersion comprises deformable colloidal particles comprising a surfactant and optionally a phospholipid, and wherein one or more deformable colloidal particles in the first colloidal dispersion contain the first target agent (CA) for use in the treatment or prevention of a disease.

According to a third aspect, the present invention provides a composition comprising a first colloidal dispersion and a second colloidal dispersion, wherein each colloidal dispersion comprises deformable colloidal particles comprising a surfactant and optionally a phospholipid, and wherein one or more deformable colloidal particles in the first colloidal dispersion contain a first target agent (CA), for cosmetic treatment of a subject or for use in skin care.

The composition can be used to treat or prevent acne. The composition can be used to treat or prevent dry skin, pruritus, skin redness, peeling skin, skin aging, skin depletion, damage to the skin around the eyes, uneven skin tone, photoaging of the skin or dermatitis. The composition can also be used for the cosmetic treatment of these conditions, i. E. to improve the appearance of the skin affected by these conditions.

Treating or preventing damage to the skin around the eyes can be treating or preventing wrinkles around the eyes (i.e. bags under the eyes), fine lines around the eyes, dark circles under the eyes, bags under the eyes, sagging skin around the eyes, excess pigmentation around the eyes or puffiness around the eyes.

The use for which the composition according to the present invention is provided depends, at least in part, on the type of the first CA and / or the second CA and / or any additional CA included in the composition.

For example, if the composition according to the first aspect of the invention contains a first non-drug colloidal dispersion, a second colloidal dispersion containing deformable colloidal particles attached to zinc stearate and additional CA, which is chlorhexidine or a salt thereof, then the composition can be used to treat or prevent acne or dermatitis. The specified composition can also be used for the treatment of skin prone to acne, in particular to prevent the appearance of acne on skin prone to acne.

Acne is a common skin condition that affects many people at various times in their lives. It can cause skin blemishes to develop, usually on the face, back and chest. The spots can range from black or white acne on the surface of the skin, which is often mild, to deep, inflamed, pus-filled acne and cysts that can be severe and cause scarring. The condition is caused by excess sebum production, which in turn leads to an increase and change in bacterial activity, which causes inflammation and the formation of pus.

Current acne treatment options include both simple cleansers and

- 11 038613 topical exfoliators and antibiotics, oral retinoid preparations, the use of which can be associated with serious side effects. In many patients, treatments are ineffective or limited by side effects. The composition according to the present invention solves these problems.

The composition may be suitable for treating or preventing acne, not only because the deformable colloidal particles increase the rate, depth, and efficiency of absorption of zinc stearate and chlorhexidine or a salt thereof into the patient's skin, but also because the colloidal particles in the first drug-free colloidal dispersions can help remove lipids from the skin by accelerating the removal of sebum. In addition, as discussed above, the attachment of zinc stearate to deformable colloidal particles lowers the regulation of sebum production in the sebaceous glands, and the inclusion of chlorhexidine in the formulation kills bacteria and controls increased bacterial proliferation. Thus, the specified composition can remove existing sebum and reduce its production by stopping the access of microorganisms to their food source, as well as by killing existing microorganisms. This group of functions helps to reduce inflammation in blemishes, repair the epidermis, remove impurities and tighten and tighten pores, which leads to a decrease in the recurrence of symptoms (such as blemishes, hormonal acne, black acne and oily skin) and further spread of infection.

If the composition according to the first aspect of the invention contains a first non-drug colloidal dispersion and a second colloidal dispersion containing deformable colloidal particles attached to zinc stearate, the composition can be used to treat or prevent redness, irritation and flaking of the skin. The colloidal particles in the first colloidal dispersion of said composition isolate sebum, and zinc stearate attached to the colloidal particles in the second colloidal dispersion reduces sebum production. This dual function reduces the colonization of secretions by microorganisms, maintains a normal skin environment and also reduces the recurrence of symptoms by stopping microorganisms from accessing their food source: the sebum on which they grow. In addition, colloidal particles deliver nutrients to the skin. Thus, the specified composition reduces redness, swelling, flaking, wetting, blistering and skin erosion caused by excess oil, and also contributes to a healthy skin balance and supports the mechanism of self-renewal and repair of the skin.

For the avoidance of doubt, the description of drug-free or void colloidal dispersions refers to dispersions free of any non-lipid surfactant CA that are used for therapeutic purposes. These colloidal dispersions may contain active agents such as antimicrobial agents, stabilizers and preservatives. However, it should be understood that these agents are used solely to increase the stability of the formulations and to improve their shelf life; they are not used for therapeutic purposes.

If the composition according to the first aspect of the invention comprises a first non-drug colloidal dispersion, a second colloidal dispersion containing deformable colloidal particles containing palmitoylcorbate, a third colloidal dispersion containing deformable colloidal particles containing palmitoyl tetrapeptide-7, and a fourth colloidal dispersion containing palmitoyltripeptide-1, the composition can be used to treat or prevent skin aging and thinning.

The symptoms associated with skin aging and thinning are detailed in various documents and publications. Accordingly, a variety of cosmetic treatments are available to address these conditions, but many of these treatments are not supported by reliable data. In addition, each of these cosmetic treatments must be applied separately to target each symptom of aging, thinning of the skin. The compositions of the present invention facilitate these methods and provide effective treatment of all symptoms of aging with a single application of the composition.

Palmitoylcorbate is a form of vitamin C that acts as an antioxidant; protects skin from free radical damage and reduces the appearance of brown sun spots, enhances normal collagen production and reduces inflammation and irritation. Palmitoyltetrapetide-7 and palmitoyltripeptide-1 inhibit the production of excess interleukins and thus inhibit excessive inflammatory responses that lead to glycation damage and increased tissue stiffness. In addition, these peptides enhance connective tissue growth, increase collagen production in the skin to normal levels and provide self-healing and skin rejuvenation. Zinc stearate and tocopherol linoleate may optionally be added to improve the characteristics of the mixture: zinc is important for slowing down the breakdown of collagen, and tocopherol (vitamin E) is an important antioxidant that can stabilize vitamin C and enhance its action. Thus, the specified composition can eliminate all visible signs of photoaging of the skin, provides a tightened appearance, clearer contours and

- 12 038613 skin elasticity. It promotes the formation of new collagen and elastin, slows down the breakdown of collagen and increases the strength of the inner structure of the skin. It also preserves the extracellular matrix of the skin, prevents free radical damage, and provides hydration and repair. It reduces small and pronounced wrinkles, bags under the eyes, dark circles, sagging skin and excess pigmentation and improves skin tone, smoothness, firmness, elasticity and overall appearance.

If the composition according to the first aspect of the invention contains a first drug-free colloidal dispersion, a second colloidal dispersion containing deformable colloidal particles containing palmitoyl ascorbate, a third colloidal dispersion containing deformable colloidal particles containing palmitoyl tetrapeptide-7, a fourth colloidal deformable dispersion containing palmitoyltripeptide-1, and a fifth colloidal dispersion containing deformable colloidal particles containing zinc stearate, the composition can be used to treat or prevent redness, dryness and itching. Redness, dryness, and itching of the skin can be caused by conditions such as atopic eczema and dyshidrotic eczema of the hands. As noted above, palmitoyl ascorbate acts as an antioxidant to prevent skin damage, peptides enhance collagen production and promote skin regeneration, and zinc acts as an antimicrobial agent and reduces sebum production and also slows down collagen breakdown. The colloidal particles themselves provide hydration to the deep layers of the skin with pure water and prevent water loss by forming a vapor-impermeable barrier within the skin structure. Thus, the function of the specified composition is to protect the skin, maintain the mechanism of self-repair of the skin and deliver nutrients to the skin to improve the normal function of the skin, which helps to prevent new exacerbations. It reduces redness, swelling, peeling, wetting, itching, skin thinning, blistering, and skin erosion, which are often symptoms of skin conditions such as eczema.

If the composition according to the first aspect of the invention contains a first colloidal dispersion containing deformable colloidal particles containing tridecylsalicylate and alpha-tocopherol or derivatives thereof, and a second colloidal dispersion containing colloidal particles containing palmitoylascorbic acid, tocopheryllinoleate and alpha-tocopherol derivatives, or a composition can be used to treat or prevent uneven skin tone. Alpha-tocopherol can be contained in the specified composition within the cavity of the colloidal particles or in the continuous phase of the composition (i.e. not associate with the colloidal particles). Tridecyl salicylate, palmitoyl ascorbic acid and tocopherol linoleate can be attached to the colloidal particle. The composition can improve the appearance of uneven skin in one or more of the following ways: by reducing wrinkles, excess pigmentation, acne, dark circles under the eyes, improving the appearance of skin texture, and increasing skin elasticity.

The composition can also be used to treat or prevent pain or discomfort as it can act as a topical anti-irritant agent.

If the composition according to the first aspect of the invention contains CA selected from glucosamine or its salt, glucosamine amide or its salt and / or chondroitin or its salt, then the composition can be used to maintain and prolong joint health and / or to treat or prevent joint diseases (arthropathy ), in particular degenerative joint diseases such as arthritis and osteoarthritis.

These formulations can also be used to treat or prevent pain associated with poor joint health.

If the composition according to the first aspect of the invention contains CA selected from glucosamine or a salt thereof, glucosamine amide or a salt thereof and / or chondroitin or a salt thereof, the composition can also be used for the preparation of a medicament for maintaining and prolonging joint health and / or for the treatment or prevention of joint diseases (arthropathy), in particular degenerative joint diseases such as arthritis and osteoarthritis, or pain associated with poor joint health.

If the composition according to the first aspect of the invention contains CA selected from glucosamine or its salt, glucosamine amide or its salt and / or chondroitin or its salt, then CA may or may not be associated (i.e., associated) with the deformable colloidal particle. If CA is associated with a deformable colloidal particle, the glucosamine derivative or its salt, glucosamine amide or its salt and / or chondroitin or its salt can be used to attach to the deformable colloidal particle (i.e., binding).

The compositions of the present invention can be used to maintain and prolong joint health and to treat or prevent joint diseases or pain associated with poor joint health, not only because deformable colloidal particles increase the speed, depth, and efficiency of CA passage into the patient's joint, but also due to the fact that the deformable colloidal particles can themselves relieve or alleviate pain, such as the pain associated with osteoarthritis, as discussed above.

Volume ratio (by weight) of individual colloidal dispersions (or intermediate agents

- 13 038613

Sequessome ™, Transfersome ™ or Tethersome) can be different for each formulation depending on the specific type of colloidal dispersion. For example, in a formulation that can be used to treat skin aging and wasting, the ratio of palmitoyl ascorbate intermediate to tetrapeptide intermediate and tripeptide intermediate can be from about 1: 1: 1 to about 2: 1. : 1, from about 1: 2: 1 to about 1: 3: 1, from about 1: 1: 2 to about 1: 1: 3, preferably from about 3: 1: 1 to about 5: 1: 1, and most preferably about 3: 1: 1. In a formulation that can be used to treat redness, dryness and pruritus, the ratio of palmitoyl ascorbate intermediate to tetrapeptide intermediate, tripeptide intermediate and zinc stearate intermediate and zinc stearate intermediate can be from about 1: 1: 1: 1 to about 2: 1: 1: 2, from about 3: 1: 1: 3 to about 3: 1: 1: 4, from about 4: 2: 2: 5 to about 5: 3: 3: 7 , preferably from about 3: 1: 1: 5 to about 4: 2: 2: 6, and most preferably about 3: 1: 1: 5. In formulations that can be used to treat redness, irritation, and peeling of skin and skin prone to acne, the ratio of the non-drug intermediate to the zinc stearate intermediate can be from about 1: 1 to about 2: 1, about 3: 1 to about 3: 2, about 3: 2 to about 4: 3, and most preferably about 1: 1.

If the formulation contains capsaicin as CA that is not associated with deformable colloidal particles, then the formulation can be used to treat or prevent one or more conditions selected from the group consisting of pain, including muscle pain, joint pain, and itching. Capsaicin stimulates nerve endings in the skin to create a warming sensation (which is not related to an actual physical change in temperature). Thus, formulations containing capsaicin can be injected into muscles or joints or any other tissue to relieve aches and pains. Formulations containing capsaicin can be used for prophylaxis, where they are applied before exercise to create a warming sensation in the skin and underlying muscles and joints and thus prevent muscle soreness. The formulations can also be applied during or after exercise to relieve aches and pains. The compositions of the present invention containing capsaicin are also provided for use as an analgesic drug or an antipruritic drug.

If the composition contains salicylic acid or a salt or ester thereof that is associated and / or not associated with colloidal particles, then the composition can also be used to treat or prevent one or more conditions selected from the group consisting of pain, including muscle pain and joint pain. pain. Salicylate is a pain reliever and has anti-inflammatory properties. Thus, the salicylate-containing formulations can be injected into muscles or joints or any other tissue to relieve aches and pains. Formulations containing salicylate can be used for prophylaxis, where they are applied before exercise to relieve pain in the skin and underlying muscles and joints. The formulations can also be applied during or after exercise to relieve aches and pains and reduce inflammation in the muscles and tissues of the joint.

Formulations containing capsaicin and salicylic acid, or a salt or ester thereof, can be used to treat or prevent one or more conditions selected from the group consisting of pain, including muscle pain, joint pain, and itching. These formulations can have an enhanced effect in the treatment of pain such as muscle pain and joint pain, as they can warm the skin and underlying muscles and joints and also provide analgesic and anti-inflammatory effects in these areas.

Formulations containing capsaicin and / or salicylic acid can be used to treat or prevent pain, not only because deformable colloidal particles increase the rate, depth, and efficiency of absorption of capsaicin and / or salicylic acid into the patient's skin, but also because the colloidal particles may by themselves relieve or alleviate pain, such as pain associated with osteoarthritis, as discussed above.

The compositions of the present invention are particularly suitable for patients with chronic long-term pain associated with joint diseases such as osteoarthritis who wish to avoid or minimize the use of pharmaceutical pain relievers.

If CA contains glucosamine or its salt, glucosamine amide or its salt and / or chondroitin or its salt, then the disease, disorder or condition is preferably a joint disease (arthropathy), in particular a degenerative joint disease such as arthritis or osteoarthritis, or pain associated with poor joint health.

The present invention also provides a method for maintaining or prolonging joint health, comprising topically applying a composition according to the first aspect of the invention to the skin of a patient in need thereof, wherein the CA contains glucosamine or a salt thereof, glucosamine amide or a salt thereof and / or chondroitin or a salt thereof. CA may or may not be associated (i.e., associated) with deformable colloidal particles. If associates are formed, glucosamine derivatives and / or chondroitin should be used.

- 14 038613

The compositions according to the present invention containing capsaicin find use in cosmetics due to their moderate irritant effect. In particular, topical application of capsaicin to the skin leads to vasodilation. When applied to lips, capsaicin causes an increase in volume and redness, which improves their appearance.

The compositions of the present invention containing salicylic acid or a salt or ester thereof and tocopherol can be used to improve the appearance of uneven skin tone by reducing excessive pigmentation such as black age spots and liver spots. Salicylic acid or its salt or ester and tocopherol can be contained in the composition, forming and not forming associates with colloidal particles. Salicylic acid or its salt or ester and tocopherol, which form associates with colloidal particles, can be attached to the colloidal particles. The attached salicylic acid can be in the form of myristyl salicylate or tridecyl salicylate, where the aliphatic myristyl chain or aliphatic tridecyl chain is enclosed within the colloidal particles. Attached tocopherol can be in the form of tocopheryllinoleate, where the linoleate chain is enclosed within colloidal particles.

The compositions of the present invention may contain colloidal dispersions containing colloidal particles containing myristyl salicylate or tridecyl salicylate, wherein myristyl salicylate or tridecyl salicylate is attached to the colloidal particle component.

The compositions according to the present invention can contain colloidal dispersions containing colloidal particles containing tocopherylline linoleate, where the tocopherylline linoleate is attached to the colloidal particle component.

These formulations may not contain any other form of salicylic acid or tocopherol. These compositions may contain one or more additional colloidal dispersions containing colloidal particles containing a different CA, such as vitamin C. Alternatively, colloidal particles containing myristyl salicylate, tridecyl salicylate or tocopheryllinoleate may also contain vitamin C. The compositions may also contain tocopherol, which does not form associates with colloidal particles (i.e. it can be contained in the continuous phase of the compositions). The formulations may also contain tocopherol in the vesicle cavity.

The compositions of the present invention may contain colloidal dispersions containing non-drug colloidal particles and myristyl salicylate or tridecyl salicylate, wherein myristyl salicylate or tridecyl salicylate does not associate with colloidal dispersions. In these formulations, myristyl salicylate or tridecyl salicylate can form micelles in the medium, which can be a separate phase other than colloidal particles.

The specified composition has a double effect. Attached salicylic acid or its salt or ester can penetrate deeper into the basal layer of the skin (where melanocytes are located), where it can act on tyrosinase and downregulate melanin production. Salicylic acid or its salt or ester, which does not form associates with deformable colloidal particles, penetrates the skin to a shallower depth, remains in the outer layers of the epidermis, where it exhibits a weak exfoliating effect, which increases the rate of formation of new skin with a reduced melanin content. Thus, the patient will be able to more quickly notice the skin lightening effects when using the attached salicylic acid or its salt or ester than in the case where the attached salicylic acid or its salt or ester is absent.

The product containing the salicylate compound can be used as a topical anti-irritant agent.

The compositions containing caffeine according to the present invention can improve the appearance of the skin, in particular the skin around the eyes. As discussed above, this is due to its action as an antioxidant and anti-inflammatory agent. In particular, caffeine has vasoconstrictor properties and is thought to constrict blood vessels that cause dark circles under the eyes. As demonstrated in Example 6, the compositions of the present invention can reduce puffiness and edema around the eyes and below the lower eyelid (bags under the eyes), dark circles under the eyes and fine lines and deep wrinkles, including crow's feet, around the eyes. The formulations can also affect skin around the eyes that looks and feels less thin, looks and feels firmer, feels more elastic, looks smoother, and is more hydrated. The formulations can also tighten sagging skin, which leads to reduced skin laxity and sagging. The formulations can even out skin tone, sharpen the appearance and feel of the eye contour, improve skin tone and tightening, and make the eyes look rested and less tired. They can also be used to prevent sun damage to the skin.

Without wishing to be bound by any particular theory, the present inventors also believe that colloidal particles themselves have a beneficial effect on the skin, in particular the skin around the eyes, as they have a nano-stenting effect that helps this sensitive tissue to remove excess fluid. The nano-stenting effect is understood as the ability of colloidal particles to act as a proppant or scaffold and to be located in the extracellular space of tissues, where they facilitate the removal of extracellular / interstitial fluids into the lymph. Colloidal particles are thought to physically expel the interstitial fluid and the by-products it contains. It helps to remove unwanted by-products into and through the lymph, which prevents the accumulation of toxic substances and also promotes the normal removal of fluid from the lymph in cases where this function is impaired.

If these compositions contain palmitoylasorbic acid and tocopherol, then they have an enhanced antioxidant effect. If these formulations contain palmitoyltripeptyl-1 and palmitoyltetrapeptide-7 attached to deformable colloidal particles, this also stimulates collagen synthesis. Thus, there is an additional improvement in the appearance of the skin around the eyes.

Compositions of the present invention containing tocopherol in a continuous phase and salicylic acid or a salt or ester thereof attached to deformable colloidal particles can improve the appearance of the skin. In particular, the compositions can be used to improve skin tone, for example by treating and / or preventing uneven skin tone.

As discussed above, tocopherol acts as a powerful antioxidant and anti-inflammatory agent, protecting the cells that produce collagen and elastin and acting as an effective moisturizer. As discussed above, salicylic acid or a salt or ester thereof can also improve uneven skin tone by reducing excess pigmentation such as black age spots and liver spots. As demonstrated in Example 7, the compositions of the present invention can reduce fine and deep wrinkles and the number and size of overpigmented / pigmented marks on the skin. The compositions can act on skin that begins to look significantly smoother and feels significantly healthier and more elastic. The compositions can promote a youthful and significantly healthier complexion, with visible improvements and brightening. The compositions also significantly even out skin tone and significantly lighten overpigmented / pigmented skin marks and dark circles around the eyes.

If these compositions contain palmitoyl ascorbic acid and tocopheryllinoleate attached to the second form of deformable colloidal particles, this enhances their antioxidant effect.

The compositions according to the present invention can be used to improve the appearance of the skin, not only because the deformable colloidal particles increase the rate, depth and efficiency of absorption of tocopherol and salicylic acid or a salt or ester thereof into the patient's skin, but also because the deformable particles themselves themselves can improve the appearance of the skin. As discussed above, deformable colloidal particles can increase the removal of interstitial fluid into the lymph nodes, which prevents the accumulation of toxic by-products in the skin.

The invention also provides the use of a composition according to the first aspect of the present invention for the preparation of a medicament for the treatment or prevention of a disease or for the cosmetic treatment of a subject or for skin care.

In all of the compositions of the present invention, the particular combination (or composition or mixture) of particular colloidal dispersions and CA, if present, provides multiple effects for the composition.

The compositions according to the present invention can be called skin cosmetics because they can eliminate the symptoms of dermatological conditions as well as mask them. Without wishing to be bound by any theory, it is believed that the flexible microscopic spheres (i.e., colloidal particles) in the composition according to the present invention, containing natural plant lipids, allow the composition to be used as an active additive for the skin to support the natural healing process. providing hydration to the deep layers of the skin with clean water and preventing water loss by forming a vapor-impermeable barrier within the skin structure. CA, if it is in the continuous phase of the composition (i.e. not associated with a deformable colloidal particle), is pushed through the skin by the deformable colloidal particles included in the composition, and any CA that is associated with the deformable colloidal particle is pulled through the skin by the deformable colloidal particles to which it is attached. This action ensures the passage of CA through the skin and delivery of effective amounts to the required sites.

The compositions according to the present invention may contain one or more vitamins. These vitamins can be attached to colloidal particles, contained in a continuous phase, or as a separate phase.

These vitamins may include vitamin C (ascorbic acid) or esters thereof, for example palmitoyl ascorbic acid or palmitoyl ascorbate. The compositions may contain 0.01 to 1.0 wt% vitamin C (ascorbic acid) or esters thereof, more preferably 0.05 to 0.5 wt%, most preferably about 0.1 wt%. Preferably vitamin C or its

- 16 038613 ester attached to deformable colloidal particles.

Another preferred vitamin that can be included in the compositions of the present invention is vitamin E (tocopherol) or its esters, for example tocopheryllinoleate. The compositions may contain from about 0.01 to 1.0 wt% vitamin E (tocopherol) or esters thereof, more preferably from about 0.05 to 0.5 wt%, most preferably from about 0.1 to 0, 2 wt%. Preferably, the tocopheryllinoleate is attached to the deformable colloidal particles. Preferably, the tocopherol is in a separate phase.

Vitamins such as vitamin C and vitamin E and their esters give the vesicles an antioxidant protective effect.

The compositions according to the present invention may simultaneously contain vitamin C and vitamin E, or their esters. Preferably, vitamin C or esters thereof and vitamin E or esters thereof, if present, are attached to individual vesicles.

The attachment of these vitamins is especially preferred if the CA, which is not associated with deformable colloidal particles, contains salicylic acid or its salt or ester, glucosamine or its salt, glucosamine amide or its salt, chondroitin or its salt, caffeine or tocopherol.

Preferably, if the composition contains salicylic acid or a salt or ester thereof, palmitoylcorbic acid and tocopheryllinoleate are attached to the deformable colloidal particles, and the tocopherol is in a separate phase. In a particularly preferred embodiment, the composition comprises two forms of deformable colloidal particles; where the first contains attached to it salicylic acid or its salt or ester, and the second contains attached to it palmitoyl ascorbic acid and tocopheryllin oleate.

Preferably, if the composition contains glucosamine or its salt, glucosamine amide or its salt and / or chondroitin or its salt, the composition further contains palmitoyl ascorbate and tocopheryllinoleate attached to deformable colloidal particles. The inclusion of said vitamins in these formulations increases the effectiveness of said formulations in maintaining and prolonging joint health and treating or preventing joint disease or pain associated with poor joint health.

Preferably, if the composition contains caffeine, palmitoyl ascorbic acid and tocopheryllinoleate are attached to the deformable colloidal particles and the tocopherol is in a separate phase.

If the formulations contain tocopherol, then a small amount of tocopherol may be contained within the cavity of the deformable colloidal particles, while the main part of the tocopherol is in the continuous phase of the formulations.

The compositions of the present invention may further comprise tripeptide-1, preferably palmitoyltripeptide-1 and / or tetrapeptide-7, preferably palmitoyltetrapeptide-7, attached to deformable colloidal particles.

The compositions may contain from about 0.0001 to 0.1 wt% tripeptide-1, preferably palmitoyltripeptide-1, more preferably from about 0.001 to 0.01 wt%, more preferably from about 0.002 to 0.008 wt%, most preferably about 0.006 wt%.

The compositions may contain from about 0.0001 to 0.01 wt% tetrapeptide-7, preferably palmitoyltetrapeptide-7, more preferably from about 0.001 to 0.01 wt%, more preferably from about 0.002 to 0.008 wt%, most preferably about 0.006 wt%.

The attachment of tripeptide-1 and tetrapeptide-7, in particular palmitoyltripeptide-1 and / or palmitoyltetrapeptide-7, to deformable colloidal particles is particularly preferred if the CA that is not associated with deformable colloidal particles is caffeine. In a particularly preferred embodiment, the composition contains three types of deformable colloidal particles; where the first type contains palmitoylcorbic acid and tocopherol attached thereto, the second contains palmitoyltripeptide-1 attached thereto, and the third contains palmitoyltetrapeptide-7 attached thereto. Tocopherol can be contained in the colloidal particle cavity or outside the colloidal particles in the continuous phase of the composition (i.e., not associate with colloidal particles).

The inclusion of palmitoyltripeptide-1 and palmitoyltetrapeptide-7 in these formulations increases their effectiveness by stimulating collagen synthesis, increasing skin elasticity and reducing wrinkles.

The composition of the present invention can be used to treat any animal. The animal to be treated can be a human, a companion animal (eg, a cat, dog, or horse), or a farm animal. If the animal to be treated is a human, the invention can be used to treat patients of any age, for example, patients between the ages of 15 and 100 years. The human patient can be a man or a woman.

As discussed above, the composition can be applied topically, making the composition of the present invention particularly effective as a cosmetic or in the treatment of conditions.

- 17 038613 leather.

The invention includes a formulation for use, such as described in this application, where any amount of the formulation can be topically applied as often as necessary, provided that it does not go beyond any restrictions imposed by the regulations regarding the use of CA in the formulations. For example, the composition can be applied one, two, three, or more times a day. Alternatively, the formulation can be administered every other day, two or three times a week, once a week, or less frequently as needed. The composition can be administered over a period of one or more weeks, for example, for at least one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, sixteen weeks, twenty-four weeks, four months, six months, eight months, ten months, one year, two or more years, or indefinitely if necessary.

Any amount of the formulation can be administered to a patient that is sufficient to treat any of the conditions described herein. For example, a formulation of the present invention can be administered to a patient at a dose of 0.1 to 10 g. The dose can be 1 to 10 g, or 1 to 5 g, or about 1, 2, 3, 4, 5, 6, 7. , 8, 9 or 10 g. The dose can be measured as the total weight of the formulation. The dose can be measured as the total weight of the phospholipid (s) and / or surfactant (s) agent (s) in the composition. The dose can be administered once or twice a day, or as often as needed. The dose can be administered one, two, three, four, five, six or seven times a week, or as often as necessary according to the present invention. The dose can be administered every day, every other day, two to three times a week, or as often as necessary according to the present invention. Preferably, the composition can be applied twice a day. A suitable amount of the formulation (i.e., any amount of the formulation that may be sufficient to treat a condition such as described herein) can be applied to the problematic area of the skin. The composition can be left to dry for up to 15 minutes.

If the composition is to be used as a cosmetic, then any amount of the composition can be topically applied to the skin as often as necessary to provide the desired effect.

The lipid in the deformable colloidal particles included in the composition may be phosphatidylcholine.

The surfactant in the deformable colloidal particles included in the composition may be polysorbate 80.

The composition may include one or more buffers, chelating agents, humectants, lubricants, antioxidants, preservatives, microbicides, antimicrobials, emollients, cosolvents, or thickeners. Thickeners can be Carbopol® (polyacrylamide) or methylcellulose.

According to a fourth aspect, the present invention provides a method for cosmetically improving the appearance of a subject, comprising administering a composition according to the present invention to the subject. Preferably, the composition is topically applied to the skin of a subject, which is preferably a human.

If the CA contains chlorhexidine or a salt thereof, the method preferably comprises improving the appearance of the subject's skin, for example, by treating or preventing acne.

If the CA contains capsaicin, the method preferably comprises cosmetic enhancement of the appearance of the lips of the subject, for example, by imparting a plumping effect to the lips.

If the CA agent contains salicylic acid or its salt or ester and / or tocopherol or its derivative, the method preferably includes improving the appearance of the skin, for example, by treating or preventing uneven skin tone, preferably by reducing excessive pigmentation.

If the CA contains caffeine, the method preferably comprises improving the appearance of the subject's skin, preferably the skin around the eyes.

If CA contains glucosamine or its salt, glucosamine amide or its salt and / or chondroitin or its salt, the method preferably includes improving the appearance of the skin, for example, by increasing collagen production to reduce fine and deep wrinkles.

According to a fifth aspect, the present invention provides a method for producing a composition according to the first aspect of the invention. Preferably, the method comprises a first preparation step in which the colloidal dispersion is prepared from an organic phase containing alcohol-soluble components and an aqueous phase consisting of water-soluble components. In a second stage of preparation, the specified initial dispersion is mixed with a thickener to obtain a gel with the desired density. CA is preferably added during said second production step. Colloidal dispersions of more than one kind can be added, so that the final composition contains more than one kind of colloidal particles.

According to a sixth aspect, the present invention provides a method of treating a disease, disorder or condition in a subject, comprising topically applying a composition comprising a first colloidal dispersion and a second colloidal dispersion, wherein each colloidal dispersion comprises deformable colloidal particles containing a surfactant and , optionally, a phospholipid, and where one or more deformable colloidal particles in the first colloidal dispersion contain the first target agent (CA), and the disease is cured.

If the CA contains chlorhexidine or a salt thereof, the disease, disorder or conditions are preferably acne or dermatitis.

If the CA contains capsaicin, the disease, disorder or condition is preferably selected from the group consisting of pain, including muscle pain, and itching.

If the CA agent contains salicylic acid or its salt or ester and / or tocopherol or its derivative, then the disease, disorder or condition is preferably pain or discomfort.

If CA contains glucosamine or its salt, glucosamine amide or its salt and / or chondroitin or its salt, then the disease, disorder or condition is a joint disease (arthropathy), in particular a degenerative joint disease such as arthritis or osteoarthritis, or pain, associated with poor joint health.

The present invention also provides a method for maintaining and prolonging joint health, comprising topically applying the composition according to the first aspect of the invention to the skin of a patient in need thereof, wherein the CA contains glucosamine or a salt thereof, glucosamine amide or a salt thereof and / or chondroitin or a salt thereof.

The present invention can be used to administer CA, such as chlorhexidine or its salt, capsaicin, salicylic acid or its salt or ester, glucosamine or its salt, glucosamine amide or its salt and / or chondroitin or its salt, caffeine or tocopherol, to the skin or through the skin of an animal. Preferably, the method comprises topically applying the composition to the skin of a patient in an amount sufficient to penetrate the skin and deliver CA.

The present invention can also be used to administer a CA, such as glucosamine or its salt, glucosamine amide or its salt and / or chondroitin or its salt, into an animal's joint, for example, the shoulder, elbow, wrist, interphalangeal, knee or ankle joint.

Preferably, the method comprises topically applying the composition to the skin of the patient in an amount sufficient to penetrate the skin and deliver the CA to the underlying joint. Any animal can be included, including humans, dogs, cats, horses, productive animals, and domestic animals.

According to a seventh aspect, the present invention provides a kit comprising one or more cells, wherein at least one cell comprises a composition comprising a first colloidal dispersion and a second colloidal dispersion, wherein each colloidal dispersion comprises deformable colloidal particles containing a surfactant and optionally , phospholipid, and where one or more deformable colloidal particles in the first colloidal dispersion contain the first target agent (CA).

Preferably, the composition according to the first aspect of the invention is in a separate compartment in said kit.

The kit can be made in such a way that it is marked with marks that indicate the amount of composition remaining or dispensed.

The kit can be in the form of a tube, serving sachet or jar. The kit may contain dispensing means, preferably selected from the group consisting of a pump, a dispensing nozzle, a measuring cup, or a spatula.

The instructions for administering the formulation according to the first aspect of the invention preferably comprise instructions for administering the formulation according to any of the second, third, fourth, fifth, or sixth aspects of the present invention.

Preferably, the instructions contain instructions for topical administration of the formulation.

The kit can be designed for use in the treatment of a disease.

If the CA contains chlorhexidine or a salt thereof, the instructions for its administration preferably include instructions for its administration to a patient or subject in need thereof for the treatment or prevention of a disease or disorder associated with the patient's skin, preferably acne or dermatitis. Alternatively, the instructions may instruct the subject to administer the composition to the skin to improve its appearance.

If the CA contains capsaicin, the instructions for its administration preferably include instructions for its administration to a patient or subject in need thereof for the treatment or prevention of pain, including muscle pain and / or itching. The instructions can also instruct the subject to administer the composition prior to exercise. Alternatively, the instructions may instruct the subject to apply the composition to the lips to provide a cosmetic bulking effect.

If the CA agent contains salicylic acid or a salt thereof, or an ester, and / or tocopherol or a derivative thereof, the instructions for their administration preferably contain instructions for their administration to a patient or subject in need thereof for the treatment or prevention of pain or discomfort. Alternatively, the instructions may instruct the subject to apply the composition to the skin to improve uneven skin tone, including excessive pigmentation.

If CA contains glucosamine or its salt, glucosamine amide or its salt and / or chondroitin or its salt, then the instructions for their administration preferably contain instructions for their administration to a patient or subject in need thereof, in order to maintain and prolong joint health and / or for treating or preventing joint diseases (arthropathy), in particular degenerative joint diseases such as arthritis and osteoarthritis, or pain associated with poor joint health. Alternatively, the instructions may instruct subjects to administer the composition to the skin to improve the appearance of the skin, for example, by reducing fine and deep wrinkles, improving skin tone, protective function, and combating excess pigmentation.

If the CA contains caffeine, the administration instructions preferably include instructions for administering it to a patient or subject in need thereof to improve the appearance of the skin, for example the skin around the eyes. The composition for improving the appearance of the skin containing caffeine may also contain tocopherol or a derivative thereof.

If CA contains tocopherol in a continuous phase and salicylic acid or a salt or ester thereof attached to deformable colloidal particles, then the instructions for their administration preferably contain instructions for their administration to a patient or subject in need of it, to improve the appearance of the skin, for example for treating and / or preventing uneven skin tone.

An eighth aspect of the present invention includes a device for transdermal drug release comprising a support layer and a layer containing a composition according to the first aspect of the present invention.

The device for transdermal drug release may contain a plate, patch, bandage or dressing.

The backing layer can be made from any suitable material, including fabric and silicone.

The device for transdermal drug release can be applied to the skin of the patient so that the layer of the composition according to the first aspect of the invention comes into contact with the skin of the patient.

The backing layer can remain on the skin for a predetermined period of time, for example from 1 hour to 3 days. Alternatively, the support layer can be removed and the composition layer remains in contact with the skin.

All preferred features of the first aspect of the invention also apply to the second, third, fourth, fifth, sixth, seventh, and eighth aspects of the invention.

In general, the nomenclature used herein and the organic chemistry, medicinal chemistry and pharmacology laboratory methods described herein are well known and routinely used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the meanings commonly known to those of ordinary skill in the art to which the present invention belongs.

As used herein, skin includes the skin of the body as a whole and any other skin such as epithelium in the ear, nose, throat, and eye, including the sclera of the eye, and other mucous membranes such as the vagina and anus / rectum.

As used herein, a sufficient amount, an amount effective for, an amount sufficient for, or an amount of a formulation sufficient to provide a particular result refers to the amount of a formulation of the present invention that is effective to achieve a desired effect, which is not necessarily a therapeutic effect (i.e. e. with the introduction of a therapeutically effective amount). In other words, a therapeutically effective amount is an amount that provides some relief, amelioration and / or amelioration of at least one clinical symptom. The clinical symptoms associated with the disorder that can be treated by the methods of the present invention are well known to those skilled in the art. In addition, those skilled in the art will understand that therapeutic effects do not have to be complete or cure if they have any beneficial effect on the subject. For example, a sufficient amount or an amount sufficient for may be an amount that is effective in treating the symptoms of any disease or condition such as described herein.

As used herein, the terms treat, treatment, or treatment mean that the severity of a subject's condition is reduced or at least partially alleviated or alleviated, and / or at least some relief, amelioration, or reduction of at least one clinical symptom, and / or suppression or delay in the progression of the condition and / or delay in the progression or onset of the disease or disease occurs. The terms treat, treatment, or method of treatment also refer to the fight against a painful condition.

- 20 038613

The term pharmaceutically acceptable, when used herein in relation to a formulation according to the present invention, means that the formulation does not cause an unacceptable level of irritation in the subject to which the formulation is administered. Preferably, the specified level should be low enough for the formulation to be approved by the regulatory authorities.

When used in the present description in relation to numerical values, the term approximately or approximately denotes a region around a particular numerical value, which includes values that would be expected given the usual experimental errors in measurement. For example, in certain embodiments, the term about, when used in relation to a particular numerical value, means +/- 20%, unless specifically indicated +/- 1, +/- 2, +/- 3, +/- 4, + / -5, +/- 10, +/- 15, or +/- 20% of a numeric value.

According to the present invention, the term comprising is inclusive or open and does not exclude additional unspecified elements or process steps; the term consisting of excludes any elements, steps or ingredients not specified; and the term consisting essentially of excludes any element, step, or ingredient that significantly alters the essential characteristics of the invention.

Colloidal particles in colloidal dispersions included in the composition according to the present invention may contain a mixture of more than one nonionic surfactant. Colloidal particles in colloidal dispersions included in the composition according to the present invention may contain a mixture of more than one phospholipid. Colloidal particles in colloidal dispersions included in the composition according to the present invention may contain a mixture of more than one nonionic surfactant and more than one phospholipid. Colloidal particles in colloidal dispersions included in the composition according to the present invention may contain at least one nonionic surfactant, at least one phospholipid, a pharmaceutically acceptable carrier, and optionally buffers, antioxidants, preservatives, microbicides, antimicrobial agents, emollients, cosolvents and / or thickeners. Colloidal particles in colloidal dispersions included in the composition according to the present invention can consist essentially of a nonionic surfactant and a phospholipid, a pharmaceutically acceptable carrier and optionally of buffers, antioxidants, preservatives, microbicides, antimicrobial agents, emollients, cosolvents and / or thickeners. Colloidal particles in colloidal dispersions included in the composition according to the present invention may consist of at least one nonionic surfactant, at least one phospholipid, a pharmaceutically acceptable carrier and one or more buffers, antioxidants, preservatives, microbicides, antimicrobial agents , emollients, cosolvents and thickeners.

Any lipid known in the art that can form a phospholipid bilayer can be used to prepare the composition of the present invention.

Table 1 lists the preferred phospholipids according to the present invention.

Table 1

Laur (o) il

Palmit (o) ooze

Stear (o) il | Begen (o) il

Eruts (o) il

Arakhin (o) silt

Gadolen (o) silt

Arachidon (o) silt

Ole (o) il

Linol (o) silt

Linole (n / a) silt Palmit (o) silt Mirist (o) sil Capr (o) silt

Preferred lipids in the context of the present invention are uncharged and form stable, well-hydrated bilayers; phosphatidylcholines, phosphatidylethanolamine and sphingomyelins are the most common examples of these lipids. Any of these lipids can have chains such as those listed in table. 1; and those that can form bilayers in the fluid phase in which the phospholipid chains are in a disordered state are preferred.

A preferred phospholipid, for example, is natural phosphatidylcholine, which was previously known as lecithin. It can be obtained from eggs (rich in palmitic, C16: 0, and oleic, C18: 1, radicals, but also containing stearic, C18: 0, palmitoleic, C16: 1, linolenic, C18: 2, and arachidonic, C20: 4 (M) radicals), soy (rich in unsaturated C18 chains, but also containing some palmitic radicals among others), coconut (rich in chains), olives (rich in monounsaturated chains), saffron (safflower) and sunflower (rich in n-6-linoleic acid), flax (rich in n-3-linolenic acid), blubber (rich in monounsaturated n-3-chains), primrose or primrose (rich in n-3-chains). The preferred natural phosphatidylethanolamines (referred to as cephalins) are often derived from eggs or soy. Preferred sphingomyelins of biological origin are generally obtained from eggs or brain tissue. Preferred phosphatidylserines are also generally obtained from the medulla, with the phosphatidylglycerol being preferably extracted from bacteria such as E. coli, or otherwise obtained by transphosphatidylation using phospholipase D using natural phosphatidylcholine as a starting material. The phosphatidylinositols used preferably are isolated from commercial soy phospholipids or bovine liver extracts. Preferably, phosphatidinic acid is extracted from any of the above sources or prepared using phospholipase D from a suitable phosphatidylcholine.

Synthetic phosphatidylcholines, synthetic phosphatidylethanolamines, synthetic phosphatidinic acids, synthetic phosphatidylserines, synthetic phosphatidyl (poly) alcohols such as phosphatidylinositol, or synthetic phosphatidylglycerol can also be used according to the present invention.

In addition, suitable lipids are a phosphatidylcholine analog such as 1-lauroyl-1,3-dihydroxypropane-3-phosphorylcholine, a monoglyceride such as monoolein or monomyristin, cerebroside, ceramide, polyhexoside, sulfatide, sphingoplasmalogen, ganglioside or which does not contain an esterified phosphoryl or phosphono or phosphino group at position 3. An example of said glyceride is diacylglyceride or 1-alkenyl-1-hydroxy-2acylglyceride with any acyl or alkenyl groups, where the 3-hydroxy group forms an ether with one of the carbohydrate groups, for example with a galactosyl group such as monogalactosylglycerol.

Lipids with the desired head or chain properties can also be obtained using biochemical agents, for example phospholipases (such as phospholipase A1, A2, B, C and in particular D), desaturases, elongases, acyltransferases, etc., from natural or synthetic precursors ...

In addition, a suitable phospholipid is any phospholipid that is present in biological membranes and can be extracted using polar organic solvents such as chloroform. In addition to the lipids already noted, these lipids also include, for example, steroids such as estradiol, or sterols such as cholesterol, beta-sitosterol, desmosterol, 7-keto-cholesterol or beta-cholestanol, fat-soluble vitamins such as retinoids, vitamins such as vitamin A1 or A2, vitamin E, vitamin K such as vitamin K1 or K2 or vitamin D1 or D3, etc.

Less soluble amphiphilic components contain, or preferably contain, a synthetic phospholipid such as myristoleoyl, palmitoleoyl, petroselinyl, petroselaidil, oleoyl, elaidil, cis- or transvaccenoyl, linolyl, linolenil, linolaidyl, octadecatetraenoyl, gondoyl, eicosyl-cyenoyl, eicosyl or transdocozaenoyl, docosadienoyl, docosatrienoyl, docosatetraenoyl, lauroyl, tridecanoyl, myristoyl, pentadecanoyl, palmitoyl, heptadecanoyl, stearoyl or nonadecanoyl, glycerophospholipid, or the corresponding derivatives with the corresponding branched chain di-alkylipolcyl or other di-branched or sphenylphospholipid or di-alkylphospholipid or other di-branched or sphenyl-di-branched chain or other di-branched chain or other di-branched chain dihydroxyphospholipids.

The more soluble amphiphilic (s) component (s) are often obtained from the less soluble components listed above, and to increase solubility, substitution is carried out and / or complexes and / or associates with butanoyl, pentanoyl, hexanoyl, heptanoyl are obtained, octanoyl, nonanoyl, decanoyl or undecanoyl substituent or with several independently selected substituents or with another substance to increase solubility.

An additional suitable phospholipid is a diacyl- or dialkylglycerophosphoethanolamine-azopolyethoxylene derivative, didecanoylphosphatidylcholine or diacylphosphooligomaltobionamide.

The amount of phospholipid in the compositions of the present invention can range from about 0 to about 12 wt%, from about 0.2 to about 10 wt%, from about 0.6 to about 8 wt%, from about 1.0 to about 7 wt%, from about 1.5 to about 6 wt%, from about 2 to about 4 wt%, from about 3 to about 3.5 wt%, or about 0.7 wt%, about 1.4 wt%, about 3.4 wt%, or about 3.6 wt%. Preferably, the phospholipid is phosphatidylcholine.

The compositions according to the present invention may contain a surfactant. The term surfactant has its usual meaning. A list of significant surfactants and definitions concerning surfactants is given in European patent EP 0475160 A1 (see, for example, pp. 6, 1.5 to 14. 1.17) and in US patent No. 6165500 (see, for example, , pillar, 7, 1.60 to 19, 1.64), and in relevant surfactant or pharmaceutical guides such as the Handbook of Industrial Commercially Active Substances

- 22 038613 (Handbook of Industrial Surfactants) or US Pharmacopoeia, European Pharmacopoeia. Surfactants can be those described in table. 1-18 in US Patent Application No. 2002/0012680 A1, published January 31, 2002. The following list thus provides a selection of certain classes of surfactants that are conventional or may be suitable for this patent application, and is by no means exhaustive or exclusive. Preferred surfactants for use in the present invention include those that have an HLB greater than 12. Included are ionized long chain fatty acids or long chain alcohols, ammonium salts of long chain fatty acids such as alkyl or alkenoyl trimethyl, dimethyl and -methyl-ammonium, alkyl- or alkenoyl-sulfate salts, dimethylamine oxides of long-chain fatty acids, such as alkyl- or alkenoyl-dimethyl-amine oxides, long-chain fatty acids, for example alkanoyl-, dimethyl-amine oxides and in particular dodecyl dimethylamine oxide, for example long-chain fatty acids N-methylglucamides and alkanoyl-N-methylglucamides such as MEGA8, MEGA-9 and MEGA-10, N-long chain fatty N, N-dimethylglycines, for example N-alkyl-N, N-dimethylglycines, 3- (long chain fatty dimethylammonium) alkane -sulfonates, for example 3 (acyldimethylammonium) alkanesulfonates, long chain fatty derivatives of sulfosuccinate salts such as bis- (2-ethylalkyl) sulfonate succinate salts, long chain fatty sulfobetaines such as acyl sulfobetaines, long chain fatty betaines such as EMPIGEN BB or ZWITTERGENT-3-16, -3-14, -3-12, -3-10 or -3-8, or simple polyethylene glycol α-acylphenyl ethers, in particular non-ethylene glycol-octylphenyl ether, long-chain fatty polyethylene ethers, in particular polyethylene acyl ethers, such as non-ethylene decyl ether, non-ethylene-dodecyl ether or octaethylene-dodecyl ether, octaethylene-dodecyl ether octaethylene glycol isotridecyl ether, long chain fatty esters of polyethylene glycol sorbitan, for example polyethylene glycol sorbitan acyl esters and in particular polyoxyethylene monolaurate (for example polysorbate 20 or Tween 20), polyoxyethylene sorbitan 80 or polyoxyoleate , polyoxyethyl ensorbitana monoelaidat, polyoxyethylene miristoleilat, polyoxyethylene palmitoleinilat, polyoxyethylene petroselinilat simple long chain fatty poligidroksietilena esters such simple poligidroksietilen-acyl ethers, such as simple poligidroksietilen-lauryl ethers, poligidroksietilenmiristoilovye ethers, poligidroksietilen-cetylstearyl ethers, poligidroksietilen-palmitic ethers, polyhydroxyethylene oleoyl ethers, polyhydroxyethylene palmitoleoyl ethers, polyhydroxyethylene linoleyl ethers, polyhydroxyethylene-4, or 6- or 8-, or 10-, or 12-lauryl, myristoyl, palmitoyl, palmitoleyl Brij series) or the corresponding esters, polyhydroxyethylene laurate, β-myristate, β-palmitate, β-stearate or α-oleate, in particular polyhydroxyethylene 8-stearate (Myrj 45) and polyhydroxyethylene 8-oleate, polyethoxylated castor oil 40 (Cremophor EL) tanmono long-chain fatty alkylate (Arlacel or Span series), in particular sorbitan monolaurate (Arlacel 20, Span 20), long-chain αcyl-N-methylglucamides, alkanoyl-N-methylglucamides, in particular decanoyl-N-methylglucamide, long-chain dodecanoyl-N-methylglucamide fatty sulfates such as alkyl sulfates, alkyl sulfate salts such as lauryl sulfate (SDS), oleoyl sulfate; long chain fatty thioglucosides such as alkylthioglucosides and in particular heptyl-, octyl-nonyl-beta-E-thioglucopyranoside; long-chain fatty derivatives of various carbohydrates such as pentoses, hexoses and disaccharides, in particular alkyl glucosides and maltoses such as hexyl, heptyl, octyl, nonyl and decyl beta-E-glucopyranoside or D-maltopyranoside; in addition, salts such as salts of fatty acids, in particular oleate, elaidate, linoleate, laurate or myristate, more often in sodium-containing form, lysophospholipids, n-octadecylene glycerophosphatidic acid, octadecylene phosphoryl glycerol, octadecylene nosphosphoryl glycerol acids as n-acyl-glycerophosphatidic acids, in particular lauryl-glycerophosphatidic acids, oleoyl-glycerophosphatidic acid, n-long chain fatty phosphorylglycerol such as n-acyl-phosphorylglycerol, in particular lauryl-, myristoyl- or palmitoleoleoleoleoleoleoleoyl- -long-chain fatty phosphorylserine, such as n-acyl-phosphorylserine, in particular lauryl-, myristoyl-, oleoyl- or palmitoleoylphosphorylserine, n-tetradecyl-glycerophosphatidinic acid, n-tetradecyl-phosphoryldecylidecyl-erylideryl , the corresponding short-chain phospholipids, as well as all surfactants and thus ohm, membrane-destabilizing polypeptides. Surfactant chains are generally selected so that they are in a fluid state, or at least can maintain a fluid state in the aggregates of the support.

The surfactant in the compositions of the present invention is a nonionic surfactant. The content of the surfactant in the composition

- 23,038613 can be from about 0 to about 1 wt%, from about 0.04 to about 0.8 wt%, from about 0.06 to about 0.6 wt%, from about 0.08 to about 0.4 wt%, about 0.1 to about 0.3 wt%, about 0.15 to about 0.2 wt%, about 0.1 to about 5 wt%, about 0 , 2 to about 3 wt%, from about 0.3 to about 4 wt%, from about 0.5 to about 10 wt%, from about 1 to about 9 wt%, from about 1.5 to about 7 wt%, about 2 to about 6 wt%, or about 3 to about 8 wt%. The nonionic surfactant can be selected from the group consisting of: polyoxyethylene sorbitans (polysorbate surfactants), polyhydroxyethylene stearates, or polyhydroxyethylene lauryl ethers (Brij surfactants). The surfactant can be polyoxyethylene sorbitan monooleate (eg Polysorbate 80 or Tween 80) or Tween 20, 40 or 60. The polysorbate can have any chain containing from 12 to 20 carbon atoms. Polysorbate containing one or more double bonds, branch sites or cyclic groups can be in a fluid state in the compositions.

The compositions according to the present invention may contain only one non-ionic surfactant. The compositions according to the present invention may contain only one phospholipid. The compositions of the present invention may contain only one nonionic surfactant and only one phospholipid. The compositions according to the present invention may contain one or more of one surfactant and / or one or more of one phospholipid, for example independently one, two, three, four surfactants or more and / or one, two, three, four phospholipids, or more.

The compositions of the present invention can have a range of lipid / phospholipid to surfactant ratios. The ratios can be expressed in terms of moles (mole lipid / mole surfactant or mole phospholipid / mole surfactant). They can also be expressed as% by weight. The weight ratio of lipid or phospholipid to surfactant in the formulation can be from about 20: 1 to about 5: 1, from about 15: 1 to about 10: 1, from about 12: 1 to about 9: 1, from about 18 : 1 to about 14: 1. In particular, the weight ratio of lipid or phospholipid to surfactant in the formulation can be about 8: 1, about 9: 1, about 10: 1, about 15: 1, or about 16: 1. Lipid or phospholipid may be absent, i.e. the ratio is 0: 1. Surfactant may be absent, i. E. the ratio is 1: 0. Preferably, all deformable colloidal particles in the composition according to the present invention have the same ratio of lipid or phospholipid to surfactant.

The compositions of the present invention may also contain varying total amounts of the following components: combinations of a lipid or phospholipid and a surfactant (TA). The amount of TA can be expressed as a percentage by weight of the total weight of the composition. TA can be from about 1 to about 40%, from about 5 to about 30%, from about 7.5 to about 15%, from about 6 to about 14%, from about 8 to about 12%, from about 5 to about 10%, about 10 to about 20%, or about 20 to about 30%. TA can be 6, 7, 8, 9, 10, 12, 14, 15 or 20%.

The molar ratio of lipid or phospholipid to surfactant in the compositions of the present invention can be from about 1: 3 to about 30: 0, from about 1: 3 to about 30: 1, from about 1: 2 to about 30: 1, from about 1: 1 to about 30: 0, from about 1: 1 to about 30: 1, from about 2: 1 to about 20: 0, from about 2: 1 to about 20: 1, from about 5: 1 to about 30: 1, about 10: 1 to about 30: 1, about 15: 1 to about 30: 1, or about 20: 1 to about 30: 1. The molar ratio of lipid or phospholipid to surfactant in the composition can be from about 1: 2 to about 10: 1. The molar ratio can be from about 1: 1 to about 2: 1, from about 2: 1 to about 3: 1, from about 3: 1 to about 4: 1, from about 4: 1 to about 5: 1, or from about 5: 1 to about 10: 1. The molar ratio can be from about 10: 1 to about 30: 1, from about 10: 1 to about 20: 1, from about 10: 1 to about 25: 1, and from about 20: 1 to about 25: 1. The ratio of lipid or phospholipid to surfactant can be about 1.0: 1.0, about 1.25: 1.0, about 1.5: 1.0, about 1.75: 1.0, about 2, 0: 1.0, about 2.5: 1.0, about 3.0: 1.0, or about 4.0: 1.0.

Selected ranges for the total amount of lipid or phospholipid and the ratio of lipid or phospholipid to surfactant (mol / mol) in the compositions of the present invention are described in Table 1 below. 2:

- 24 038613

table 2

Total amount and ratio of lipid / phospholipid to surfactant

TA (%) Lipid / surfactant or phospholipid / surfactant (mol / mol) from 5 to 10 1.0 to 1.25 from 5 to 10 from 1.25 to 1.72 from 5 to 10 1.75 to 2.25 from 5 to 10 from 2.25 to 3.00 from 5 to 10 from 3.00 to 4.00 from 5 to 10 from 4.00 to 8.00 from 5 to 10 from 10.00 to 13.00 from 5 to 10 from 15.00 to 20.00 from 5 to 10 from 20.00 to 22.00 from 5 to 10 from 22.00 to 25.00 from 10 to 20 1.0 to 1.25 from 10 to 20 from 1.25 to 1.75 from 10 to 20 from 1.25 to 1.75 from 10 to 20 from 2.25 to 3.00 from 10 to 20 from 3.00 to 4.00 from 10 to 20 from 4.00 to 8.00 from 10 to 20 from 10.00 to 13.00 from 10 to 20 from 15.00 to 20.00 from 10 to 20 from 20.00 to 22.00 from 10 to 20 from 22.00 to 25.00

The compositions of the present invention may optionally contain one or more of the following ingredients: cosolvents, chelating agents, buffers, antioxidants, preservatives, microbicides, emollients, humectants, lubricants and thickeners. Preferred amounts of optional components are described in the following table. 3.

Table 3

Molar concentration (M) or Rel. mass% * Antioxidant: Primary: Bottled hydroxyanisole, BHA 0.1-8 Butylated hydroxytoluene, BHT 0.1-4 Thymol 0.1-1 Metabisulfite 1-5 mM Bisulfite 1-5 mM Thiourea (MM = 76.12) 1-10 mM Monothioglycerin (MW = 108.16) 1-20 mM Propyl gallate (MM = 212.2) 0.02-0.2 Ascorbate (MM = 175.3 ⁺ ion) 1-10 mM Palmitylascorbate 0.01-1 Tocopherol-PEG 0.5-5 Secondary (chelating agent) EDTA (MM = 292) 1-10 mM EGTA (MM = 380.35) 1-10 mM Desferal (MM = 656.79) 0.1-5 mM Buffer Acetate 30-150 mM Phosphate 10-50 mM Triethanolamine 30-150 mM * - percentage of the total amount of phospholipid.

The composition according to the present invention is generally prepared and / or administered in an aqueous medium. The composition can be prepared with or without co-solvents such as lower alcohols. The composition according to the present invention can also contain a polar liquid medium. The composition may be in the form of a solution, suspension, emulsion, cream, lotion, ointment, gel, spray, film-forming solution, or varnish. Preferably, the composition according to the present invention is in the form of a gel.

The composition according to the present invention may include a buffer to adjust the pH of the aqueous solution in the range of pH 3.5 to pH 9, pH 4 to pH 7.5, or pH 6 to pH 7. Examples of buffers include, but are not limited to, acetate buffers, lactate buffers, phosphate buffers, and propionate buffers. Preferably, the compositions contain one or more buffers selected from the group consisting of disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dehydrate, sodium dihydrogen phosphate dodecahydrate, and a phosphate buffer, eg, phosphate buffer (pH 6.7).

A microbicide or antimicrobial agent is usually added to reduce the number of bacteria

- 25 038613 in pharmaceutical formulations. Examples of microbicides are short-chain alcohols including ethyl and isopropyl alcohol, chlorobutanol, benzyl alcohol, chlorobenzyl alcohol, dichlorobenzyl alcohol, hexachlorophene; phenolic compounds such as cresol, 4-chloro-m-cresol, p-chloro-mxylenol, dichlorophene, hexachlorophene, povidone iodine; parabens, in particular alkyl parabens such as methyl, ethyl, propyl or butyl paraben, benzyl paraben; acids such as sorbic acid, benzoic acid and their salts; quaternary ammonium compounds such as alconium salts such as bromide, benzalkonium salts such as chloride or bromide, cetrimonium salts such as bromide, phenoalkecinium salts such as phenododecinium bromide, cetylpyridinium chloride and other salts; in addition, mercury compounds such as phenylmercury acetate, borate or nitrate, thiomersal, chlorhexidine or its gluconate, or any compounds having antibiotic activity, biological origin, or any suitable mixtures.

Examples of antioxidants are butylhydroxyanisole or butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and di-tert-butylphenol (LY178002, LY256548, HWA-131, BF-389, CI-986, BI-127443, E-51 or -L-239XX, etc.), tert-butylhydroquinone (TBHQ), propyl gallate (PG), 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ); aromatic amines (diphenylamine, palkylthio-o-anisidine, ethylenediamine derivatives, carbazole, tetrahydroindenoindole); phenols and phenolic acids (guaiacol, hydroquinone, vanillin, gallic acids and their esters, protocatechuic acid, quinic acid, syringic acid, ellagic acid, salicylic acid, nordihydroguairetic acid (NDGA), eugenol); tocopherols (including tocopherols (alpha, beta, gamma, delta) and derivatives thereof such as tocopheryl acylate (e.g. acetate, laurate, myristate, palmitate, oleate, linoleate, etc., or any other suitable tocopheryl lipoate), tocopheryl POE- succinate; troloc and the corresponding amide and thiocarboxamide analogs; ascorbic acid and its salts, isoascorbate, (2 or 3 or 6) -o-alkylcorbic acids, ascorbyl esters (for example, 6-o-lauroyl-, myristoyl-, palmitoyl-, oleoyl- or linoleoyl-L-ascorbic acid, etc.) It is also preferable to use oxidized compounds such as sodium bisulfite, sodium metabisulfite, thiourea; chelating agents such as EDTA, HDTA, desferal: auxiliary endogenous defense systems such as transferrin, lactoferrin, ferritin, ceruloplasmin, haptoglobin, hemopexin, albumin, glucose, ubiquinol-10; enzymatic antioxidants such as superoxide dismutase and metal complexes with similar activities, including catalase, glutathione eroxidases and less complex molecules such as beta-carotene, bilirubin, uric acid; flavonoids (flavones, flavonols, flavonones, flavanonals, chalcones, anthocyanins), N-acetylcysteine, mesna, glutathione, diohistidine derivatives, triazoles; tannins, cinnamic acid, hydroxycinnamic acids and their esters (coumaric acids and esters, caffeic acid and its esters, ferulic acid, (iso) chlorogenic acid, sinapic acid); spice extracts (eg, clove, cinnamon, sage, rosemary, nutmeg, oregano, allspice, nutmeg); carnosic acid, carnosol, corosolic acid; rosmarinic acid, rosmarindiphenol, gentisic acid, ferulic acid; oat flour extracts such as avenanthramide 1 and 2; thioethers, dithioethers, sulfoxides, tetralkylthiuram disulfides; phytic acid, steroid derivatives (eg U74006F); tryptophan metabolites (for example, 3-hydroxykynurenine, 3hydroxyanthranilic acid) and organic chalcogenides.

Thickeners used to increase the viscosity of pharmaceutical compositions can be selected from pharmaceutically acceptable hydrophilic polymers such as partially esterified cellulose derivatives containing carboxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropylmethyl, or methylcellulose; fully synthetic hydrophilic polymers such as polyacrylates (e.g. Carbopol®, in particular Carbopol 974P), polymethacrylates, poly (hydroxyethyl) -, poly (hydroxypropyl) -, poly (hydroxypropylmethyl) methacrylate, polyacrylonitrile, methylallyl sulfonate, polyethylenes, polyoxyethylenes, polyethylene glycols, polyethylene glycol lactide, polyethylene glycol diacrylate, polyvinyl pyrrolidone, polyvinyl alcohols, poly (propyl methacrylamide), poly (propylene fumarate ethylene glycol), poloxamers, polyaspartamide (cross-linked hyduronic acid), hyaluronic acid natural gums including alginates, carrageenan, guar gum, gelatin, tragacanth, (amidated) pectin, xanthan, chitosan, collagen, agarose; mixtures thereof and derivatives or copolymers and / or other pharmaceutically or at least biologically acceptable polymers. Preferred thickeners used in the compositions of the present invention can be selected from Carbopol® (Carbopol® 974P NF), methylcellulose (Metolose SM 4000), Keltrol CG-T (xanthan gum for personal use), Xantural 11k (xanthan gum for pharmaceutical use ), hydroxypropyl ethyl cellulose, Genuvisco CG-131 (carrageenan gum), Kelcogel (gellan gum), Sucraclear HC-31 (cellulose gum, carrageenan, Ceratonia siliqua gum, sucrose), Sucrathix VX (microcrystalline cellulose), cellulose (glyceryl acrylate / acrylic acid) or chitosan.

One particularly preferred formulation according to the present invention contains insoluble aggregates or micelles of chlorhexidine or a salt thereof, preferably chlorhexidine digluco-26,038613 nate, together with empty deformable colloidal particles, preferably empty Sequessome ™, and deformable colloidal particles, preferably Tethersome, to which is attached zinc stearate.

Another particularly preferred formulation according to the present invention contains liposomes containing capsaicin, menthol and phospholipids together with deformable colloidal particles, preferably Transfersome ™, whose membranes contain menthol.

A particularly preferred composition comprises myristyl salicylate or tridecyl salicylate dissolved in the continuous phase and deformable colloidal particles, preferably Tethersome, to which myristyl salicylate or tridecyl salicylate is attached. Preferably, the tocopherol derivative is also attached to said deformable colloidal particles. This composition further contains a second type of deformable colloidal particles, preferably Tethersome, to which palmitoyl ascorbic acid and tocopheryllinoleate are attached. Tocopherol can be contained in the continuous phase of the composition.

Another particularly preferred formulation contains glucosamine hydrochloride and chondroitin sulfate dissolved in the continuous phase and deformable colloidal particles, preferably Tethersome, to which palmitoyl ascorbate and tocopheryllinoleate are attached.

An additional particularly preferred formulation comprises N-acetylglucosamine sulfate and chondroitin sulfate dissolved in the continuous phase and deformable colloidal particles, preferably Tethersome, to which palmitoyl ascorbic acid and tocopheryllinoleate are preferably attached.

Another particularly preferred composition comprises caffeine dissolved in the continuous phase and deformable colloidal particles, preferably Tethersome, to which palmitoyl ascorbic acid and tocopheryllinoleate are preferably attached. In addition, the specified composition contains two additional types of deformable colloidal particles, the first, to which palmitoyltripeptide-1 is attached, and the second, to which palmitoyltetrapeptide-7 is attached. Preferably, the composition contains tocopherol in a separate phase. A small amount of tocopherol can be trapped in the cavities of the deformable colloidal particles. One of the options for the implementation of the specified composition is shown in example 6.

An additional particularly preferred formulation contains deformable colloidal particles containing tridecylsalicylate and / or alpha-tocopherol. The tridecyl salicylate is preferably attached to the colloidal particles. Alpha-tocopherol may be contained in the continuous phase of the formulations (i.e., it does not associate with colloidal particles), and some may be trapped in the colloidal particle cavity. In addition, the specified composition contains an additional type of deformable colloidal particles containing palmitoylcorbic acid, tocopheryllinoleate and / or alpha-tocopherol. Palmitoyl ascorbic acid and tocopheryllinoleate are preferably attached to the colloidal particle. Alpha-tocopherol may be contained in the continuous phase of the formulations (i.e., not associate with colloidal particles), and some may be trapped in the colloidal particle cavity. One of the options for the implementation of the specified composition is shown in example 7.

In the following, the invention will be described using the following examples and figures, in which:

in fig. 1 shows the structure of a colloidal particle (vesicle or Sequessome ™ / Transfersome ™ / Tethersome) according to the present invention. The spherical bilayer may contain a surfactant or lipid, or a surfactant and a lipid. As you can see, in the above diagram, the double layer is two molecules wide;

in fig. 2 shows a typical composition according to the first aspect of the invention. The specified composition contains a colloidal dispersion (or an intermediate agent Sequessome ™ / Transfersome ™ / Tethersome) containing colloidal particles, where the colloidal dispersion contains colloidal particles containing the target agent (CA) (for example, a peptide, ascorbic acid or zinc), and CA, which does not form associates with colloidal particles (for example, chlorhexidine or capsaicin);

in fig. 3 is a table that summarizes the data on the proposed compositions 1-4;

in fig. 4 shows the change in sebum level from baseline on day 0 (= 100%);

in fig. 5 shows the percentage change in the number of comedones compared to the amount on day 0 (100%);

in fig. 6 shows the percentage change in the number of acne compared to the number on day 0 (100%);

in fig. 7 shows a reduction in measurable wrinkle volume and a reduction in fine and deep wrinkles after treatment with two types of formulations according to the present invention;

in fig. 8 compares the reduction in wrinkle volume (as a percentage of volume at baseline at week 0) after treatment with a formulation of the present invention, a UK-made flagship product (market product), and a control;

in fig. 9 shows a comparison of the reduction in the perceived size of deep and fine wrinkles (in

27,038,613% by volume at baseline at week 0) after treatment with a formulation according to the present invention, a UK-made flagship product (market product) and a control; and in FIG. 10 compares the reduction in dark circles around the eyes (as a percentage of volume at baseline at week 0) after treatment with a formulation of the present invention, a UK-made flagship product (marketed), and a control.

Examples of

Example 1. Method of obtaining.

A simplified general method for preparing the compositions of the present invention is set forth below. In a first step, colloidal dispersions are prepared containing deformable colloidal particles (eg, Sequessome ™ intermediate, Transfersome ™ intermediate, or Tethersome intermediate). Each of these colloidal dispersions is prepared from an organic phase containing alcohol-soluble components and an aqueous phase consisting of water-soluble components. In a second step, a gel (thickener) phase is obtained in which the colloidal dispersion (s) are dispersed. During this second stage, more than one type of colloidal dispersion is introduced (where each type contains different CAs (or additional ingredients) associated with the colloidal particles to give them unique characteristics), as a result of which the final thickened product is a mixture of one or more separate types of vesicles (or colloidal particles). CA or additional ingredients may include zinc stearate, palmitoyl peptides, palmitoyl ascorbic acid (PAA), myristyl salicylate, tridecyl salicylate, vitamin D or vitamin E, etc. (attached ingredients). If desired, CA that is not associated with colloidal particles can be added to the gel phase in the second stage of preparation. If desired, the first phase of the preparation process can be carried out in such an order as to obtain one or more compositions containing colloidal dispersions containing colloidal particles without any CA, and then CA (attached to a [phospho] lipid or surface active substance). The second phase in the gel is then carried out as described above.

Primary production method: Organic phase

Phospholipon 90K Polysorbate 80 Benzyl alcohol Melting

Methylparaben ____ ingredients when

Ethylparaben stirring

Linalool at 35-55 ° С

VNT Ethanol (additional ingredients) ''

Water phase

Buffer salts

EDTA disodium

Adding buffering water ingredients in h ------ (additional homogenizer and ingredients) stirring at 35-55 ° С

Adding the organic phase to the aqueous phase in a homogenizer over 30 minutes

I

Homogenization within 1 hour

Isolating the Sequessome Intermediate Agent

I

[Sequessome intermediate agent - process stop)

Secondary method of obtaining:

Gel phase

Water

Glycerin ___________ Adding buffering ingredients to the homogenizer and

Buffer salts stirring at 25 ° C

Thickener | (eg Carbopol 974P NF) —► Adding thickener and mixing thoroughly to dispense pH adjuster (if required); ¹

Dissolve with stirring * Neutralize thickener (if required) by titration to desired pH

Intermediate agent (s) Add intermediate agent (s)

Sequessome ► Sequessome into gel for 15 minutes and mix thoroughly

Isolation of the final product into an intermediate container before filling / packaging

- 28 038613

Example 2. The proposed compositions.

Suggested composition 1

Organic phase - intermediate Quantity required per 100 g 1600ppm PAA agent final product (g) SPC 4.12200 Ethanol 2.19660 VNT 0.01200 Methyl 4-hydroxybenzoate 0.15000 Ethyl 4-hydroxybenzoate 0.15000 Benzyl alcohol 0.31500 Polysorbate 80 0.40800 PAA 0.09600 Linalool 0.06000 Organic phase, total 7,50960 The aqueous phase is an intermediate agent 1600 rrt RAA Sodium metabisulfite 0.03000 Lemon acid 0.04320 EDTA Na 0.06000 Di-Na hydrogen phosphate 12H2O 0.17280 Water 27.18420 Water phase, total 27.49020 Tethersome Intermediate Agent with PAA, total amount 34.99980

Organic phase - intermediate agent ZOORT tetrapeptide SPC 1.37400 Ethanol 0.74120 VNT 0.0040 Methyl 4-hydroxybenzoate 0.05000 Ethyl 4-hydroxybenzoate 0.05000 Benzyl alcohol 0.10500 Polysorbate 80 0.15300 Palmitoyl peptide 0.00600 Linalool 0.02000 Organic phase, total 2.50320 The aqueous phase is an intermediate agent ZOORT tetrapeptide Sodium metabisulfite 0.01000 Lemon acid 0.01440 EDTA Na 0.02000 Di-Na hydrogen phosphate 12H2O 0.05760 Water 9.06140 Water phase, total 9.16340 Tethersome Intermediate Agent with tetrapeptide, total 11.66660 Organic phase - intermediate ZOORT tripeptide agent SPC 1.37400 Ethanol 0.74120 VNT 0.00400 Methyl 4-hydroxybenzoate 0.05000 Ethyl 4-hydroxybenzoate 0.05000 Benzyl alcohol 0.10500 Polysorbate 80 0.15300 Palmitoyl peptide 0.00600 Linalool 0.02000 Organic phase, total 2.50320 The aqueous phase is an intermediate agent ZOORT tripeptide Sodium metabisulfite 0.01000

- 29 038613

Lemon acid 0.01440 EDTA Na 0.02000 Di-Na hydrogen phosphate 12H2O 0.05760 Water 9.06140 Water phase, total 9.16340 Tethersome intermediate with tripeptide, total 11.66660 Total number of intermediate Tethersome agents 58.33300 Gel phase - final product Sodium hydroxide 0.11300 Carbopol 974Р 0.75000 Glycerol 3.00000 Lemon acid 0.05600 Di-Na hydrogen phosphate 12H2O 0.24200 Water 37.50600 Gel phase, total 41.66700 Total 100,00000

Suggested composition 2

Organic phase - intermediate Quantity required per 100 g 1600ppm PAA agent final product (g) SPC 2.06100 Ethanol 1.09830 VNT 0.00600 Methyl 4-hydroxybenzoate 0.07500 Ethyl 4-hydroxybenzoate 0.07500 Benzyl alcohol 0.15750 Polysorbate 80 0.20400 PAA 0.04800 Linalool 0.03000 Organic phase, total 3.75480 The aqueous phase is an intermediate agent 1600 rrt RAA Sodium metabisulfite 0.01500 Lemon acid 0.02160 Di-Na hydrogen phosphate 12H2O 0.08640 Water 13.62210 Water phase, total 13.74510 Tethersome Intermediate Agent with PAA, Total 17.49990 Organic phase - intermediate agent ZOORT tetrapeptide SPC 0.68700 Ethanol 0.37060 VNT 0.00200 Methyl 4-hydroxybenzoate 0.02500 Ethyl 4-hydroxybenzoate 0.02500 Benzyl alcohol 0.05250 Polysorbate 80 0.07650 Palmitoyl peptide 0.00300 Linalool 0.01000 Organic phase, total 1.25160 The aqueous phase is an intermediate agent ZOORT tetrapeptide Sodium metabisulfite 0.00500 Lemon acid 0.00720 Di-Na hydrogen phosphate 12H2O 0.02880 Water 4.54070 Water phase, total 4.58170 Tethersome Intermediate Agent with tetrapeptide, total 5.83330 Organic phase - intermediate ZOORT tripeptide agent SPC 0.68700 Ethanol 0.37060 VNT 0.00200 Methyl 4-hydroxybenzoate 0.02500 Ethyl 4-hydroxybenzoate 0.02500 Benzyl alcohol 0.05250

- 30 038613

Polysorbate 80 Palmitoylpeptide Linalool Organic phase, total 0.07650 0.00300 0.01000 1.25160 The aqueous phase is an intermediate agent ZOORT tripeptide Sodium metabisulfite 0.00500 Lemon acid 0.00720 Di-Na hydrogen phosphate 12H2O 0.02880 Water 4.54070 Water phase, total 4.58170 Tethersome Intermediate Agent with tripeptide, total 5.83330 Organic phase - intermediate zinc stearate agent SPC 3.43500 Ethanol 1.82850 VNT 0.01000 Methyl 4-hydroxybenzoate 0.12500 Ethyl 4-hydroxybenzoate 0.12500 Benzyl alcohol 0.26250 Polysorbate 80 0.34000 Zinc stearate 0.08200 Linalool 0.05000 Organic phase, total 6,25800 The aqueous phase is an intermediate agent with zinc stearate Sodium metabisulfite 0.02500 Lemon acid 0.03600 Di-Na hydrogen phosphate 12H2O 0.14400 Water 22.70350 Water phase, total 22.90850 Tethersome Intermediate Agent with zinc, total 29.16650 The total number of intermediate Tethersome agents 58.33300 Gel phase - final product Sodium hydroxide 0.11300 Carbopol 974Р 0.75000 Glycerol 3.00000 Lemon acid 0.05600 Di-Na hydrogen phosphate 12H2O 0.24200 Water 37.50600 Gel phase, total 41.66700 Total 100,00000

Suggested composition 3

Organic phase - empty Quantity required per 100 g Sequessome intermediate agent final product (g) SPC 3.57300 Ethanol 1.75000 VNA 0.01000 Methyl 4-hydroxybenzoate 0.12500 Ethyl 4-hydroxybenzoate 0.12500 Benzyl alcohol 0.26250 Polysorbate 80 0.23600 Linalool 0.05000 Organic phase, total 6.13150 Water phase - empty intermediate agent Sequessome Dihydrogen phosphate Na 2H2O 0.22200 Di-Na hydrogen phosphate 12H2O 0.38600 Water 34.02100 Water phase, total 34.62900 Sequessome empty intermediate agent, Total 40.76050

The organic phase is an intermediate with zinc stearate

- 31 038613

SPC 3.57300 Ethanol 1,66800 VNA 0.01000 Methyl 4-hydroxybenzoate 0.12500 Ethyl 4-hydroxybenzoate 0.12500 Benzyl alcohol 0.26250 Polysorbate 80 0.23600 Zinc stearate 0.08200 Linalool 0.05000 Organic phase, total 6.13150 The aqueous phase is an intermediate agent with zinc stearate Dihydrogen phosphate Na 2H2O 0.22200 Di-Na hydrogen phosphate 12H2O 0.38600 Water 34.02100 Water phase, total 34.62900 Tethersome Intermediate Agent with zinc, total 40.76050 Total number of intermediate agents Sequessome and Tethersome 81.52100 Gel phase - final product Sodium hydroxide 0.30000 Carbopol 974Р 1.00000 Glycerol 3.00000 Water 14,17900 Gel phase, total 18.47900 Total 100,00000

Suggested composition 4

Organic phase - empty Quantity required per 100 g Sequessome intermediate agent final product (g) Soy Phosphatidylcholine (SPC) 3.43500 Ethanol 1.82550 VNA 0.01000 Methyl 4-hydroxybenzoate 0.12500

Ethyl 4-hydroxybenzoate 0.12500 Benzyl alcohol 0.26250 Polysorbate 80 0.42500 Linalool 0.05000 Organic phase, total 6,25800 Water phase - empty intermediate agent Sequessome Citric acid monohydrate 0.03600 Di-Na hydrogen phosphate 12H2O 0.14400 Water 22.72850 Water phase, total 22.90850 Sequessome empty intermediate agent, Total 29.16650 The organic phase is an intermediate agent with zinc stearate Soy Phosphatidylcholine SPC 3.43500 Ethanol 1.74350 VNA 0.01000 Methyl 4-hydroxybenzoate 0.12500 Ethyl 4-hydroxybenzoate 0.12500 Benzyl alcohol 0.26250 Polysorbate 80 0.42500 Zinc stearate 0.08200 Linalool 0.05000 Organic phase, total 6,25800 The aqueous phase is an intermediate agent with zinc stearate Citric acid monohydrate 0.03600 Di-Na hydrogen phosphate 12H2O 0.14400 Water 22.72850 Water phase, total 22.90850 Tethersome Intermediate Agent with zinc, total 29.16650 Total number of intermediate agents Sequessome and Tethersome 58.33300

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Gel phase - final product Citric acid monohydrate 0.05600 Di-Na hydrogen phosphate 12H2O 0.24200 Methylcellulose (4000 cps, 88000 MM) 1.75000 Glycerol 3.00000 Water 36.00600 Gel phase, total 40.16700 Chlorhexidine digluconate 1.50000 Total 100,00000

Example 3. A study of the use of healthy volunteers to study the efficacy of two proposed chlorhexidine-containing formulations against spots on the skin, by objective instrumental measurement of sebum level and subjective visual assessment of the spread of lesions compared with placebo after 3 weeks of use.

Comparison was made of the effectiveness of Formulation 4 and the second formulation (Formulation 4.2) with a control product in terms of the ability to control sebum levels and reduce the area of acne in acne-prone individuals.

The proposed formulations (n = 36 and n = 37) contained empty Sequessome ™ and Tethersome with attached zinc and other excipients, including chlorhexidine as an antimicrobial preservative. Sequessome ™ in the two formulations had different SPCTween (polysorbate) ratios to assess the effect of this parameter on product performance. The control product did not contain vesicles, zinc or chlorhexidine (n = 20).

Data overview.

The study evaluated the efficacy and safety of Formulation 4 and Formulation 4.2 versus placebo (control) in healthy volunteers with oily and blemish-prone skin, which was confirmed by a clinical trial assistant prior to enrollment in the study.

The volunteers were assessed at the center on days 3, 7, 14 or 21, or received entirely subjective data at home.

A total of 224 volunteers completed the 3-week study: 37 received Formulation 4, 36 received Formulation 4.2, and 20 received placebo. Objective assessment included measuring the level of sebum on the face, photographing Visia CR (which was used to assess pore size and skin smoothness) and counting lesions (comedones, microcysts, papules and acne). Subjective assessment was carried out using the self-perception questionnaire (SPQ).

The sebum level decreased by more than 20% from baseline after 1 week of application of Formulation 4 and by more than 50% after 3 weeks of treatment (see Fig. 4). Published data have shown that a 30-50% reduction in sebum production is correlated with a reduction in acne symptoms. ^{1 The} number of comedones (blocked pores) was also reduced with Formulation 4: 50% of baseline after 1 week and more than 80% after 3 weeks (see FIG. 5). It is important to note that the number of acne was reduced by 90% from baseline after 1 week, and they actually disappeared after 3 weeks of treatment (see Fig. 6).

These objective measurements were additionally confirmed by the results of subjective assessment. Additional subjects were given sample formulations and questionnaires to fill out, with the sample size for each group increasing to 102 subjects, including:

82% reported a reduction in spot pain,

80% claimed that the skin became less shiny,

76% felt a reduction in blackheads,

75% reported a decrease in swelling in the spots,

75% noted that the spots did not reappear.

Composition 4 was well tolerated, there were no reports of AEs, and no erythema was observed in the study area.

This study demonstrates that Formulation 4 is very effective in the treatment of acne. The reduction in sebum and blemishes and blackheads after 21 days also confirms the effect of Formulation 4 in preventing further recurrence of symptoms.

As noted, objective measurements have shown that, compared to the control product, the test products:

significantly reduced the level of sebum on the skin surface (up to 50%);

significantly reduced comedones;

significantly reduced the number of papules and acne.

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Overall results

Table 4

The result of an objective assessment Composition 4.2 Composition 4 Decrease in sebum levels 1 week> 20%; 3 1 week> 20%; 3 across... weeks> 50% weeks> 50% Reduction of comedones through ... 1 week> 40%; 3 weeks> 90% 1 week = 50%; 3 weeks> 80% Reducing acne through ... 1 week = 90%; 3 weeks> 98% 1 week> 90%; 3 weeks> 98% Subjective assessment results:% of consonants / completely consonants Reduced blackheads 64.7% 76.5% Product has stopped repeated 69.6% 74.5% the appearance of spots Reduction of pain in spots (with 66.7% 82.4% touch) Reducing swelling in spots 73.5% 75.5% Less shiny skin 59.8% 80.4% Reducing oily sheen on the skin 67.6% 77.5% Less oily skin 69.6% 75.5%

The results obtained confirm the multifunctionality of the composition. It is assumed that the colloidal particles in the formulations help to remove excess sebum from the surface of the skin and at the same time, passing through the skin, they transfer the chlorhexidine present in the solution into the skin structure and thereby destroy bacteria. Attached zinc may also be involved in reducing sebum production and / or antimicrobial function.

Ways.

Table 5

General protocol

Name: A study of the use of two test formulations in healthy volunteers to examine the efficacy of two test formulations against skin blemishes by objective instrumental measurement of sebum levels and a subjective visual assessment of the spread of lesions compared with placebo after 3 weeks of use Study design: Simple blind, intragroup comparative Study groups: Composition 4 2 CBL-DERM-14-005-E Composition 4 CBL-DERM-006-F The two formulations studied were identical except that the colloidal particles had a slightly different SPC: Tween ratio. Control: placebo. CBL-DERM-14-007 / 8-P Introduction mode: Study groups followed a 12-week treatment regimen according to a specific treatment regimen Study duration: 21 day. Number of subjects: 36 subjects completed the active phase in group 1, 37 subjects in group 2, and 20 subjects completed the assessment in group 3. Study duration: Study Start: Week Commencing January 26, 2015 Completion of the study: in the week ending 20 Feb 2015 Research Center: Princeton Consumer Research Ltd. 307 College Road East Princeton New Jersey 08540

Investigated compositions.

1. Composition 4.2 And composition 4 (CBL-DERM-14-OO5-E and CBL-DERM-006-F). Soy phosphatidylcholine, butylhydroxyanisole, ethanol, zinc stearate, methyl 4-hydroxybenzoate, ethyl 4-hydroxybenzoate, benzyl alcohol, polysorbate 80, chlorhexidine digluconate, citric acid monohydrate, anhydrous sodium hydrogenorthophosphate, 97

- 34 038613 glycerin, linalool, water.

The applied amount of each component is shown in the tables below. Formulation 4 (CBL-DERM-14006-F) was the same as the proposed formulation given for the above formulation 4, except that Formulation 4 (CBL-DERM-14-006-F) contained carbopol instead of methylcellulose ( but in the same amount) and 0.11300 g of sodium hydroxide (the amount of water in the gel phase is changed accordingly).

2. Control (CBL-DERM-14-007 / 8-P).

Methyl 4-hydroxybenzoate, ethyl 4-hydroxybenzoate, citric acid monohydrate, disodium hydrogen phosphate dodecahydrate, sodium hydroxide, carbopol 974p (carbomer), water.

General information about the compositions.

General description of composition 4 (CBL-DERM-14-006-F)

Ingredient Amount required per 100 g of final product (g) SPC (dry weight) 6,870 Polysorbate 80 0.850 Benzyl alcohol 0.525 Methyl 4-hydroxybenzoate 0.250 Ethyl 4-hydroxybenzoate 0.250 Butylhydroxyanisole 0.020 Linalool 0.100 Disodium hydrogen phosphate 12 H ₂ O 0.530 Citric acid monohydrate 0.128 Glycerol 3,000 Ethanol 3.569 Sodium hydroxide 0.113 Carbopol 974PNF 0.750 Water 81,463 Target Agent - attached to Tethersome Zinc stearate 0.082 Target agent. - contained in the continuous phase Chlorhexidine digluconate (20% solution) " 1.5 pH 5.5

** -% for salt.

General description of the composition 4.2 (CBL-DERM-14-OO5-E)

Ingredient Amount required per 100 g of final product (g) SPC (dry weight) 7.146 Polysorbate 80 0.472 Benzyl alcohol 0.525 Methyl 4-hydroxybenzoate 0.250 Ethyl 4-hydroxybenzoate 0.250 Butylhydroxyanisole 0.020 Linalool 0.100 Disodium hydrogen phosphate 12 H ₂ O 0.530 Citric acid monohydrate 0.128 Glycerol 3,000 Ethanol 3.418 Sodium hydroxide 0.113 Carbopol 974PNF 0.750 Water 81,716 Target agent. - attached to Tethersome Zinc stearate 0.082 Target agent. - contained in the continuous phase Chlorhexidine digluconate (20% solution) " 1.5 pH 5.5

** -% for salt.

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General description of control (CBL-DERM-14-007 / 8-P)

Ingredient Amount required per 100 g of final product (g) SPC (dry weight) Polysorbate 80 Benzyl alcohol Methyl 4-hydroxybenzoate 0.250 Ethyl 4-hydroxybenzoate 0.250 Butylhydroxyanisole Linalool Disodium hydrogen phosphate 12H2O 0.530 Citric acid monohydrate 0.128 Glycerol Ethanol Sodium hydroxide 0.150 Carbopol 974PNF 1,000 Water 97,692 Target agent. - attached to Tethersome Zinc stearate Target agent. - contained in the continuous phase Chlorhexidine digluconate (20% solution) " pH 5.5

** -% for salt.

Details of the compositions.

Composition 4 (CBL-DERM-14-006-F)

Organic Phase - Empty Sequessome Intermediate Amount required per 100 g of final product (g) SPC 3.43500 Ethanol 1.82550 BHA 0.01000 Methyl 4-hydroxybenzoate 0.12500 Ethyl 4-hydroxybenzoate 0.12500 Benzyl alcohol 0.26250 Polysorbate 80 0.42500 Linalool 0.05000 Organic phase, total 6,25800 Aqueous Phase - Empty Sequessome Intermediate Citric acid monohydrate 0.03600 Di-Na hydrogen phosphate 12H2O 0.14400 Water 22.72850 Water phase, total 22.90850 Empty intermediate Sequessome agent, total 29.16650

- 36 038613

The organic phase is an intermediate with zinc stearate SPC 3.43500 Ethanol 1.74350 VNA 0.01000 Methyl 4-hydroxybenzoate 0.12500 Ethyl 4-hydroxybenzoate 0.12500 Benzyl alcohol 0.26250 Polysorbate 80 0.42500 Zinc stearate 0.08200 Linalool 0.05000 Organic phase, total 6,25800 Aqueous phase - intermediate with zinc stearate Citric acid monohydrate 0.03600 Di-Na hydrogen phosphate 12H2O 0.14400 Water 22.72850 Water phase, total 22.90850 Tethersome intermediate with zinc, total 29.16650 Total number of intermediate agents Sequessome and Tethersome 58.33300 Gel phase - final product Citric acid monohydrate 0.05600 Di-Na hydrogen phosphate 12H2O 0.24200 Sodium hydroxide 0.11300 Carbopol 974Р 0.75000 Glycerol 3.00000 Water 36.00600 Gel phase, total 40.16700 Chlorhexidine digluconate 1.50000 Total 100,00000

Composition 4.2 (CBL-DERM-14-005-E)

Organic Phase - Empty Sequessome Intermediate Amount required per 100 g of final product (g) SPC 3.57300 Ethanol 1.75000 VNA 0.01000 Methyl 4-hydroxybenzoate 0.12500 Ethyl 4-hydroxybenzoate 0.12500 Benzyl alcohol 0.26250 Polysorbate 80 0.23600 Linalool 0.05000 Organic phase, total 6.13150 Aqueous Phase - Empty Sequessome Intermediate Citric acid monohydrate 0.06400 Di-Na hydrogen phosphate 12H2O 0.26500 Water 34.30000 Water phase, total 34.62900 Empty intermediate Sequessome agent, total 40.76050 The organic phase is an intermediate with zinc stearate SPC 3.57300 Ethanol 1,66800 VNA 0.01000 Methyl 4-hydroxybenzoate 0.12500 Ethyl 4-hydroxybenzoate 0.12500 Benzyl alcohol 0.26250 Polysorbate 80 0.23600 Zinc stearate 0.08200 Linalool 0.05000 Organic phase, total 6.13150 Aqueous phase - intermediate with zinc stearate Citric acid monohydrate 0.06400 Di-Na hydrogen phosphate 12H2O 0.26500 Water 34.30000

- 37 038613

Water phase, total 34.62900 Tethersome intermediate with zinc, total 40.76050 Total number of intermediate agents Sequessome and Tethersome 81.52100 Gel phase - final product Sodium hydroxide 0.11300 Carbopol 974Р 0.75000 Glycerol 3.00000 Water 13,11600 Gel phase, total 16.97900 Chlorhexidine digluconate 1.50000 Total 100,00000

Results.

Objectively measured parameters.

Decrease in sebum levels.

Table 6

Average decrease in sebum level index relative to day 0. Negative index indicates an increase in sebum level

η Day 3 Day 7 Day 14 Day 21 Composition 4.2 36 20.47 34.94 71.64 90.11 Composition 4 37 14.51 36.30 85.35 98.49 Control twenty -21.30 -48.60 -40.35 -44.95 1 and 2 meaning R 0.0163 0.6767 0.2065 0.3936 1 and control in t- 7.04E-16 5.27E-23 9.74E-11 5.69E-16 2 and control test 1.06E-14 1.62E-24 1.10E-14 4.63E-17

For all time points, both formulations under study significantly reduced sebum levels compared to controls with p <0.1%. On day 3, formulation 4.2 performed better than formulation 4 with p <0.02. There were no significant differences in the effectiveness of the two studied formulations at all subsequent time points.

By day 21, both test formulations reduced the mean sebum level to less than 50% of baseline (see FIG. 4).

Reduction of comedones.

Table 7

Average decrease in the number of comedones relative to day 0. A positive index indicates an increase in comedones

η Day 3 Day 7 Day 14 Day 21 Composition 4.2 36 -1.44 -2.31 -2.92 -3.44 Composition 4 37 -1.14 -1.97 -2.84 -3.38 Control twenty 1.20 1.30 1.25 0.35 1 and 2 meaning R 0.414 0.468 0.903 0.934 1 and 2 in t- 235E-06 2.98E-06 4.66E-05 6.63E-04 1 and 2 test 108E-07 2.93E-05 7.20E-05 8.97E-05

For all time points, both formulations under study significantly reduced comedones compared to controls with p <0.1%. There were no significant differences in the effectiveness of the two studied formulations at all time points (see Fig. 5).

Reduction of papules.

Table 8

Analysis of progression in participants who had acne on day 0

NS Day 0 Day 3 Day 7 Day 14 Day 21 5 13 5 1 0 0 7 16 nine 5 0 0 4 ten nine eight 5 3

For those participants who started the trial with at least one papule, all treatments provided a papule reduction after 21 days.

Table 9

Probability in U-statistic (Mann-Whitney test) calculated to reduce lesions relative to day 0

DZ and D0 D7iD0 D14iD0 D21 and DO 1 and 2 0.146 0.044 0.373 0.373 1 and control 0.043 0.019 0.056 0.089 2 and control 0.110 0.093 0.110 0.254

Using a statistical test (U), formulation 4.2 was shown to perform better than control, @ <5% on day 3 and day 7, and @ <10% on day 14 and day 21, and compared to formulation 4 , @ <5% on day 7. Formulation 4 performed better than control, @ <10% on day 7.

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Reducing acne.

Table 10

A decrease in the number of acne relative to day 0. A positive index indicates an increase in the number of acne

η Day 3 Day 7 Day 14 Day 21 Composition 4.2 36 -1.28 -1.97 -2.11 -2.17 Composition 4 37 -0.92 -1.49 -1.57 -1.59 Control twenty 0.60 0.05 0.15 -0.75 1 and 2 meaning R 0.127 0.221 0.228 0.226 1 and control in t- 2.71 E-08 2.00E-05 9.67E-05 1.37E-02 2 and control test 8.60E-07 7.48E-04 1.04E-03 9.15Е-02

For all time points, from day 3 to day 14, both test formulations significantly reduced the number of acne compared to the control with p <0.1%. On day 21, formulation 4.2 still performed better than control with p <2.0%; composition 4 gave a better result compared to control with p <10%. There were no statistical differences in the efficacy of the two formulations under study at all time points (see Fig. 6).

Links.

1. Janiczek-Dolphin N1, Cook J., Thiboutot D., Harness J., Clucas A .: Can sebum reduction predict acne outcome? Br J Dermatol. 2010 Oct; 163 (4): 683-8. doi: 10.1111 / j.1365-2133.2010.09878.

Example 4: Research on rejuvenation. General description of studies and results.

Short description.

Conducted two trials of new products to measure the effectiveness and feel and perception of consumers. See fig. 7-10.

PROAWR1: A home use study showing subjective and objective improvement in wrinkles and skin appearance after treatment with two different formulations containing the same ingredients, applied in three different regimens.

PROAWR2: Study of home use in three parallel groups of preferred composition and regimen versus commercially available comparison product (marketed product A) and control (placebo).

The formulations tested in the two trials contained the same ingredients, obtained by stirring a mixture of Sequessome-based vesicles (ie, colloidal particles), some of which had additional fragments attached to the vesicle membrane.

Main results.

PROAWR1.

100% of participants following all three regimens experienced measurable reduction in wrinkle size after the first week.

The mean index of reduction in wrinkle size relative to that measured at baseline and the reduction of wrinkles relative to the index at baseline were significant (p <0.001) from the first week.

The average reduction in actual wrinkle size was 17.46% at week 12; the average Glogau index (appearance) declined by 25.86% over the period.

Based on the results of a subjective assessment:

100% reported that the skin felt smoother, healthier, and looked and felt fuller after 8 weeks.

Over 90% reported smoother, healthier-looking skin, felt more elastic, and reduced eye bags and circles.

80.8% of the participants stated that after 8 weeks their skin began to look 5-15 years younger; 50% said their skin was starting to look 10-15 years younger.

PROAWR2.

For all three independently assessed indicators (actual size of wrinkles, condition of fine and deep wrinkles, and condition of dark circles around the eyes).

The test composition and the commercial product (market product A) gave significantly improved results compared to the control in all three parameters - no improvement was observed in the control group.

The investigated composition had equal efficiency with the market commercial product (market product A).

PROAWR1. A home use study demonstrating improvement in wrinkle and skin appearance after administration of a composition according to the present invention to healthy subjects with aged and thinned skin.

Short description.

Conducted a test of two anti-aging compositions corresponding to the proposed composition 1, in a diluted and concentrated form. In the concentrated version, attached ascorbate and attached peptides were contained at twice the concentration compared to the diluted

- 39 038613 option.

The objective of this initial study was to assess the effectiveness of the inclusion of these attached fragments in the formulations and the possible effect of their concentration and application mode on the objective characteristics and subjective perception of the study participants.

Three modes were investigated:

Diluted formulation: applied twice a day to the entire face and neck.

Concentrated formulation: applied once a day to selected fine and deep wrinkles.

Combination: Participants following this regimen used both products as above.

The results showed that in the combination treatment, 100% of participants following all three regimens experienced measurable reduction in wrinkle size after the first week;

mean index of reduction in wrinkle size relative to that measured at baseline and reduction of wrinkles relative to index at baseline were significant (p <0.001) from the first week;

the average reduction in actual wrinkle size was 17.46% at week 12; the average Glogau index (appearance) declined by 25.86% over the period.

Based on the results of subjective assessment

100% reported feeling smoother, healthier, and fuller-looking and plumper skin after 8 weeks;

over 90% reported smoother, healthier skin, felt more elastic, and reduced bags and under-eye circles;

80.8% of the participants stated that after 8 weeks their skin began to look 5-15 years younger; 50% said their skin was starting to look 10-15 years younger.

Table 11

General protocol

Name: A randomized study of home use in three parallel groups of 30 healthy volunteers with wrinkles to evaluate the efficacy of two anti-aging products and one rejuvenation regimen. Simple, blind, intragroup, full-face comparison study. Study groups: Group Investigated product Mode Group 1. n = 26 DH3943 Used twice a day, morning and evening, applying an even layer on the face and neck Group 2. n = 27 DH3942 Applied once a day in the evening to selected fine or deep wrinkles Group 3. n = 26 DH3943 and DH3942 Apply DH 3943 twice a day evenly on the face and neck Once a day, apply a small amount of DH3942 to selected fine or deep wrinkles Study duration: The administration period was 12 weeks, assessed at baseline at weeks 1, 2, 4, 6, 8 and 12. Study Start: Week Commencing Aug 11, 2014 Survey Completion: Week Ending November 21, 2014 Number of subjects: 79 subjects completed the study by week 8. 62 subjects completed the 4-week extension at week 12. Way: Subjects underwent profilometry and were given a checklist, patient diary, and study item at week 0 (baseline). Subjects returned to the study center at weeks 1, 2, 4, 6 and 8 for profilometry. Aging and dark circles under the eyes were visually assessed at baseline and at weeks 1, 2, 4, 6, and 8. Subjects completed the SPQ at week 4 and week 8. DIC (Image Digitization) was performed on approximately 40% of the subjects in each group on baseline at weeks 2, 4 and 8. The study was extended by 4 weeks, where participants in groups 1 and 2 were instructed to continue using the product and undergo additional profilometry and visual examination at week 12. 50% of participants in group 3 were instructed to continue. using the regimen, with the remaining 50% receiving instructions for using the mild moisturizer. After being evaluated at week 12, subjects were compensated for the time and inconvenience and completed the study. Research Center: Princeton Consumer Research Ltd. Harbor House 23 Chandlers Quay Maldon CM9 4LF United kingdom

- 40 038613

Table 12

Investigated products

DH3943- DH3942- "Diluted" "concentrated" Soy Phosphatidylcholine Soy Phosphatidylcholine Butyl hydroxytoluene Butylhydroxytoluene Sodium metabisulfite Sodium metabisulfite Lemon acid Lemon acid Disodium hydrogen phosphate dodecahydrate Disodium hydrogen phosphate dodecahydrate Sodium EDTA Sodium EDTA Methyl 4-hydroxybenzoate Methyl 4-hydroxybenzoate Ethyl 4-hydroxybenzoate Ethyl 4-hydroxybenzoate Benzyl alcohol Benzyl alcohol Polysorbate 80 Polysorbate 80 Sodium hydroxide Sodium hydroxide Carbopol 974Р Carbopol 974Р Glycerol Glycerol Ethanol Ethanol Water Water Ascorbyl palmitate Ascorbyl palmitate * Palmitoyltripeptide-1 Palmitoyltripeptide-1 * Palmitoyltetrapeptide-7 Palmitoyltetrapeptide-7 * Linalool Linalool

* - in DH3942, these three components were contained in double the concentration compared to DH3943. DH3942 has the same composition as the typical composition of the proposed composition 1, see above.

Results.

Influence on the size of wrinkles.

100% of the participants reported a reduction in the size of their wrinkles.

Table 13

Average wrinkle size at time t, expressed as a percentage of the average size at time 0 (= 100%). The standard deviation is shown in parentheses. The P-value is the t-test result compared with the data obtained at week 0

Weeks 1 2 4 6 eight 12 DH3943 "diluted" 96.9% (1.3%) p <0.001 93.8% (1.6%) p <0.001 91.9% (1.9%) p <0.001 90.5% (1.9%) p <0.001 89.0% (2.1%) p <0.001 DH3942 - "concentrated" 96.3% (2.1%) p <0.001 93.7% (2.7%) p <0.001 90.8% (2.7%) p <0.001 88.8% (2.7%) p <0.001 87.1% (2.7%) p <0.001 Diluted + concentrated 96.5% (0.9%) p <0.001 92.7% (1.1%) p <0.001 88.9% (1.5%) p <0.001 85.2% (1.7%) p <0.001 82.3% (1.9%) p <0.001 83% (1.9%) p <0.001

Influence on the Glogau index (condition of fine and deep wrinkles).

Glogau indices are used to assess the condition of fine and deep wrinkles by independent experts.

Table 14

Average Glogau index at time t, expressed as a percentage of the mean at time 0 (= 100%). The standard deviation is shown in parentheses. The P-value is the t-test result compared with the data obtained at week 0

Weeks 1 2 4 6 eight 12 DH3943 "diluted" 99.2% (3.9%) p = 0.163 100% (0.0%) but 99.6% (2.0%) p = 0.163 95.4% (7.0%) p = 0.001 88.8% (8.9%) p <0.001 DH3942 - "concentrated" 99.2% (4.3%) p = 0.163 98.8% (4.3%) p = 0.081 96.5% (7.3%) p = 0.008 94.7% (8.9%) p = 0.001 93.1% (12.0%) p = 0.002 Diluted + concentrated 95.7% (6.3%) p <0.001 91.8% (7.7%) p <0.001 87.7% (7.6%) p <0.001 86.5% (8.6%) p <0.001 81.5% (10.0%) p <0.001 73.8% (10.4%) p <0.001

Results of subjective questionnaires.

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Table 15% of subjects agreeing / completely agreeing with the statement DH 3942 conc. DH 3943 - par. Combination

Ned. Ned.

Approval 4 8 Weeks 4 weeks 8 weeks 4 weeks eight

Feels smoother 23.1% 50.0% 30.3% 81.5% 46.2% 100.0 % Looks smoother 26.9% 61.5% 55.6% 70.4% 30.8% 96.2% Smoother tone 50.0% 92.3% 29.6% 74.1% 15.4% 88.5% Reduced acne scars 19.2% 84.6% 37.0% 55.6% 11.5% 38.5% Reduced stains 26.9% 73.1% 29.6% 100.0% 3.9% 80.8% Improved complexion 30.8% 61.5% 22.2% 100.0% 7.7% 76.9% The complexion is brighter 19.2% 38.5% 29.6% 96.3% 23.1% 88.5% Reduced age spots / excess pigmentation 26.9% 53.9% 55.6% 55.6% 61.5% 88.5% Feels firmer 38.5% 50.0% 55.6% 92.6% 42.3% 80.8% Looks firmer 19.2% 53.9% 22.2% 40.7% 34.6% 100.0 % Feels more voluminous 30.8% 57.7% 40.7% 100.0 % 19.2% 100.0 % Looks more voluminous 19.2% 46.2% 59.3% 92.6% 34.6% 100.0 % 95 Complexion looks more healthy 42.3% 76.9% 25.9% 92.6% 23.1% 96.2% Skin feels healthier 53.9% 61.5% 74.1% 88.9% 42.3% 100.0 The skin feels more elastic 46.2% 73.1% 55.6% 70.4% 26.9% 92.3% Reduced bags / circles 30.8% 57.7% 44.4% 96.3% 30.8% 92.3% The most effective anti-aging agent used 42.3% 76.9% 55.6% 81.5% 30.8% 76.9% I will use instead of the one I am currently using 46.2% 69.2% 55.6% 92.6% 65.4% 92.3% Easy to use compared to existing products 46.2% 80.8% 100.0 % 96.3% 34.6% 61.5% I will recommend to a friend / girlfriend 65.4% 76.9% 81.5% 100.0 % 73.1% 100.0 ___% Buy a product 38.5% 76.9% 18.5% 81.5% 84.6% 92.3% The skin looks younger 20+ years 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 15+ years 0.0% 3.9% 0.0% 3.7% 0.0% 7.7% 10+ years 3.9% 19.2% 7.4% 22.2% 3.9% 42.3% 5+ years 23.1% 42.3% 81.5% 55.6% 42.3% 30.8% Looks also 73.1% 34.6% 11.1% 18.5% 50.0% 19.2%

PROAWR2. A randomized study of home use in three parallel groups of 30 healthy volunteers with wrinkles to evaluate the efficacy of one anti-aging product versus placebo and a comparison agent, in which an additional 73 subjects were subjectively tested using the product alone.

Short description.

In the present test, the preferred test anti-aging formulation of the present invention (concentrated formula in the PROAWR1 study) was investigated and compared with a commercially available anti-aging commercial product (market product A) and a control formulation.

The purpose of this study was to verify:

a) that the results previously obtained for the preferred formulation were valid (control comparison);

b) to evaluate the effectiveness in comparison with the currently marketed anti-aging composition.

According to the results, it was shown that for all three independently assessed indicators (the actual size of wrinkles, the state of fine and deep wrinkles and the state of dark circles around the eyes), the studied composition and the commercial product gave significantly improved results compared to the control in all three indicators - in the control group. no improvement was observed;

the investigated composition had equal effectiveness with the commercial product on the market.

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When subjectively evaluating the products, the composition under study and the commercial product gave significantly improved results compared to the control in all parameters;

The test formulation was rated higher than the commercial product in the following categories:

the skin looks smoother, the skin feels plumper, the skin feels healthier, the skin feels more elastic, the complexion looks healthier, the skin tone looks more even, reduce eye puffiness, effectively rejuvenate, tighten sagging skin, moisturize the skin, reduce pore size.

Table 16

General protocol

Name: A randomized study of home use in three parallel groups of 30 healthy volunteers with wrinkles to evaluate the efficacy of one anti-aging product versus placebo and a comparison agent, where an additional 70 subjects were subjectively tested using the product exclusively Study design: Simple, blind, intragroup, full-face comparison study Study groups: Group Investigated product Mode Group 1. Investigated composition • Apply twice a day • Apply all over the face and neck • Apply an additional amount to areas where wrinkles / aging are most noticeable • Apply a thin layer to the bags under the eyes Group 2. Control Group 3. Market product A Study duration: Administration Period 8 weeks, estimated at baseline at week 4 week 8. Study Start: Week Commencing February 16, 2015 Survey Completion: Week Ending April 24, 2015 Way: Subjects underwent profilometry and were given a checklist, patient diary, and study item at week 0 (baseline). Subjects returned to the study center at weeks 1, 2, 4, 6, and 8 for profilometry. When subjects returned to the study center at week 8, they returned any unused study items and completed patient diaries. Aging and dark circles were visually assessed at baseline and at weeks 1, 2, 4, 6 and 8. Subjects completed the SPQ at week 8. Approximately 40% of subjects in each group were surveyed at baseline and at week 1. 2, 4 and 8, where in group 1 the maximum possible number of subjects was photographed, exceeding 40%. 70 subjects were also given the product for home use during the study period and completed the SPQ at the same time as in the active groups. Research Center: Princeton Consumer Research Ltd. Harbor House 23 Chandlers Quay Maldon CM9 4LF United kingdom

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Investigated products

Table 17

Investigated composition Control Phosphate id and l hol in soy Butylhydroxytoluene Ethanol Methyl 4-hydroxybenzoate Methyl 4-hydroxybenzoate Ethyl 4-hydroxybenzoate Ethyl 4-hydroxybenzoate Benzyl alcohol Polysorbate 80 Linalool Ascorbyl palmitate Palmitoyltripeptide-1 Palmitoyltetrapeptide-7 Sodium metabisulfite Citric acid monohydrate Citric acid monohydrate Disodium hydrogen phosphate anhydrous Disodium hydrogen phosphate anhydrous Sodium EDTA Sodium hydroxide Sodium hydroxide Carbopol 974Р Carbopol 974Р Glycerol Water Water

Results.

Influence on the size of wrinkles.

Table 18

Average wrinkle size at time t, expressed as a percentage of the average size at time 0 (= 100%). The standard deviation is shown in parentheses. The P-value is the t-test result compared with the data obtained at week 0

η Week 1 Week 2 Week 4 Week 6 Week 8 Investigated composition 27 95.9% (2.0%) p <0.001 93.1% (2.9%) p <0.001 90.7% (3.6%) p <0.001 88.8% (3.9%) p <0.001 87.5% (4.1%) p <0.001 Control 28 100.2% (1.0%) P = 0.31 100.5% (2.0%) P = 0.17 100.3% (2.9%) P = 0.57 100.4% (3.0%) P = 0.51 100.5% (3.3%) P = 0.39 Market product A 29 95.8% (2.5%) p <0.001 92.9% (3.3%) p <0.001 90.5% (3.8%) p <0.001 88.1% (4.1%) p <0.001 86.2% (4.3%) p <0.001

Table 19

P-values for t-tests when comparing different treatments

Week 1 Week 2 Week 4 Week 6 Week 8 Investigated composition and control p <0.001 p <0.001 p <0.001 p <0.001 p <0.001 Investigated composition and market product A p = 0.554 p = 0.623 p = 0.604 p = 0.817 p = 0.947 Market product A and control p <0.001 p <0.001 p <0.001 p <0.001 p <0.001

The investigated composition and market product A gave significantly improved results compared to the control.

There were no significant differences between the studied composition and the market product A.

Influence on the Glogau index (condition of fine and deep wrinkles)

Glogau indices are used to assess the condition of fine and deep wrinkles by independent experts.

Table 20

Average Glogau index at time t, expressed as a percentage relative to the average at time 0 (= 100%). The standard deviation is shown in parentheses. The p-value is the t-test result compared with the data obtained at week 0

η Week 1 Week 2 Week 4 Week 6 Week 8 Investigated composition 27 92.6% (8.5%) p <0.001 90.7% (8.3%) p <0.001 79.5% (9.8%) p <0.001 78.5% (8.9%) p <0.001 73.9% (7.4%) p <0.001 Control 28 101.7% (10.8%) p = 0.81 100.0% (10.7%) p = 0.79 102.8% (8.0%) p = 0.21 105.0% (13.4%) p = 0.12 103.9% (12.8%) p = 0.31 Market product A 29 91.6% (8.1%) p <0.001 88.9% (8.4%) p <0.001 82.2% (8.5%) p <0.001 79.9% (9.5%) p <0.001 74.3% (10.5%) p <0.001

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Table 21

P-values for t-tests when comparing different treatments

Week 1 Week 2 Week 4 Week 6 Week 8 Investigated composition and control p = 0.266 p = 0.198 p = 0.004 p <0.001 p <0.001 Investigated composition and market product A p = 0.976 p = 0.998 p = 0.681 p = 0.698 p = 0.799 Market product A and control p = 0.318 p = 0.245 p = 0.018 p = 0.005 p = 0.001

Study formulation and market product A provided a significant difference from control starting at week 4.

There were no significant differences between the studied composition and the market product A. Effects on dark circles around the eyes.

Table 22

Average index of dark circles around the eyes (PO) at time t, expressed as a percentage of the average at time 0 (= 100%). The standard deviation is shown in parentheses.

The p-value is the result of a t-test, which was compared with the data obtained at week 0

η Week 1 Week 2 Week 4 Week 6 Week 8 Investigated composition 27 72.2% (34.9%) p <0.001 48.1% (37.9%) p <0.001 38.9% (42.4%) p <0.001 29.6% (42.2%) p <0.001 27.8% (37.6%) p <0.001 Control 28 100% (0%) p = N / O 112.5% (44.4%) p = 0.49 114.3% (54.2%) p = 0.79 119.6% (59.8%) p = 0.63 121.4% (58.4%) p = 0.45 Market product A 29 77.6% (34.3%) p <0.001 56.9% (43.8%) p <0.001 34.5% (40.3%) p <0.001 34.5% 42.5%) p <0.001 31.0% (41.0%) p <0.001

Table 23

P-values for t-tests when comparing different treatments

Week 1 Week 2 Week 4 Week 6 Week 8 Investigated composition and control p = 0.013 p <0.001 p <0.001 p <0.001 p <0.001 Investigated composition and market product A p = 0.949 p = 0.589 p = 0.794 p = 0.562 p = 0.962 Market product A and control p = 0.008 p <0.001 p <0.001 p <0.001 p <0.001

Study formulation and market product A provided significant differences compared to control starting at week 1.

There were no significant differences between the studied composition and the market product A.

Results of subjective questionnaires.

Table 24

Composition under study Ν = 27 + 73 * Market product A No. 26 Control No. 28 After using the product my skin felt much smoother 82.00% 89.66% 28.57%

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my skin started to look much smoother 85.00% 55.17% 46.43% my skin felt much firmer 89.00% 89.66% 42.86% my skin looks much firmer 54.00% 58.62% 46.43% my skin felt much fuller 86.21% 25.00% my skin looks much more voluminous 56.00% 68.97% 25.00% my skin feels much healthier 86.00% 79.31% 46.43% my skin felt more elastic 83.00% 82.76% 28.57% my complexion has noticeably improved 58.00% 65.52% 25.00% my complexion has become noticeably brighter 61.00% 82.76% 21.43% my complexion has become much healthier 90.00% 86.21% 32.14% my skin tone is much smoother 90.00% 79.31% 25.00% any age spots / traces of excessive pigmentation are significantly reduced 67.00% 72.41% 46.43% bags under the eyes have decreased significantly 89.00% 35.71% puffiness around the eyes is significantly reduced 88.00% 86.21% 39.29% dark circles under the eyes are significantly reduced 86.00% 89.66% 42.86% sagging skin has become tightened 89.00% 86.21% 46.43% my skin looks like: at least 5 years younger 76.00% 82.76% 39.29% at least 10 years younger 35.00% 34.48% 0.00% Product... reshaped saggy skin 58.00% 75.86% 28.57% has a pleasant smell 62.00% 58.62% 42.86% has a pleasant consistency and texture 79.31% 32.14% has a pleasant appearance 61.00% 65.52% 28.57% feels good on the skin after or during application 66.00% 65.52% 32.14% dries quickly 89.00% 32.14% easy to use compared to conventional skin care products 86.21% 28.57% is the most effective anti-aging serum I have used. 86.00% 62.07% 39.29% re-emphasized the contours of the face, which were sagging 67.00% 72.41% 39.29% moisturized the skin 86.21% 25.00% noticeably reduced pore size 85.00% 68.97% 17.86% markedly reduced the size of the reticular veins 69.00% 75.86% 25.00% I AM... I will recommend the product to a friend / girlfriend 79.00% 32.14% I will buy this product instead of the usual anti-aging serum 57.14%

* - In addition, 73 subjects used the test formulation and completed a self-assessment questionnaire, but did not independently assess the size of wrinkles, the condition of wrinkles or the condition of dark circles around the eyes.

Example 5. Study of volunteers to study the sensation of using a formulation containing capsaicin.

State of the art.

There are several products on the market that provide a warming sensation when applied to a joint or muscle to relieve acne or pain. These products contain chemicals such as capsaicin, which stimulate the nerves in the skin to create a warming sensation (which is not related to an actual physical change in temperature).

We have developed a capsaicin-containing formulation according to the present invention, wherein a warming sensation is associated with the product, upon application, or some time after application. The formulation provides the combined effect of non-drug colloidal dispersions having pain relieving properties in combination with a warming sensation.

Formulation (TP2) contained insoluble and inflexible liposomes containing capsaicin and menthol in combination with Transfersome ™ containing menthol.

Transfersome ™ / Sequessome ™ / Tethersome are flexible deformable colloidal

- 46 038613 particles that themselves penetrate the skin, whereas liposomes are hard vesicles that normally cannot penetrate the skin on their own without the application of some other force (e.g. Sequessome ™ / Transfersome ™ / Tethersome contained in the same mixture , open pores and push / pull liposomes).

The starting material used to prepare TP2 is shown below.

TP2 (PD-14-0073) was prepared using 90 g of starting material 1 by adding / mixing with 10 g of starting material 2.

Starting material 1 (Flexible empty vesicles with menthol flavor)

Organic Phase - Empty Transfersome Intermediate SPC (dry weight) Ethanol VNT Methyl 4-hydroxybenzoate Ethyl 4-hydroxybenzoate Benzyl alcohol Polysorbate 80 Capsaicin Menthol Organic phase, total Amount required per 100 g of final product (g) 6.87000 3.65100 0.02000 0.25000 0.25000 0.52500 0.85000 0.00000 0.10000 12.51600 Aqueous phase - empty intermediate agent Transfersome Sodium dihydrogen phosphate 2Н ₂ О Disodium hydrogen phosphate 12Н ₂ О sodium EDTA Water 0.03700 0.45300 0.10000 45.22700

Water phase, total 45.81700 Intermediate agent Transfersome, total 58.33300 Gel phase - final product Sodium dihydrogen phosphate 2H ₂ O 0.02400 Disodium orthohydrogen phosphate 12H ₂ O 0.30200 Sodium hydroxide 0.63000 Carbopol 974Р NF 1.25000 Glycerol 3.00000 Water 36.46100 Gel phase, total 41.66700 Total 100,00000

Starting material 2 (capsaicin liposomes)

Organic phase - intermediate Quantity required per 100 g of final liposome product (g) SPC (dry weight) 6.87000 Ethanol 4.25100 VNT 0.02000 Methyl 4-hydroxybenzoate 0.25000 Ethyl 4-hydroxybenzoate 0.25000 Benzyl alcohol 0.52500 Polysorbate 80 0.00000 Capsaicin 0.25000 Menthol 0.10000 Organic phase, total 12.51600 Water phase - intermediate liposome Sodium dihydrogen phosphate 2H ₂ O 0.03700 Disodium hydrogen phosphate 12H ₂ O 0.45300 Sodium EDTA 0.10000 Water 45.22700 Water phase, total 45.81700 Intermediate liposome, total 58.33300 Gel phase - final product Sodium dihydrogen phosphate 2H ₂ O 0.02400 Disodium hydrogen phosphate 12H ₂ O 0.30200 Sodium hydroxide 0.63000 Carbopol 974Р NF 1.25000 Glycerol 3.00000 Water 36.46100 Gel phase, total 41.66700 Total 100,00000

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General formula

Name Starting material 1 Starting material 2 PD-14-0073 Ingredient (90% starting material 1 and 10% starting material 2 SPC (dry weight) 6.870 g 6.870 g 6.870 g Polysorbate 80 0.850 g - 0.765 g Benzyl alcohol 0.525 g 0.525 g 0.525 g Methyl 4-hydroxybenzoate 0.250 g 0.250 g 0.250 g Ethyl 4-hydroxybenzoate 0.250 g 0.250 g 0.250 g Butylhydroxytoluene 0.020 g 0.020 g 0.020 g EDTA disodium 0.100 g 0.100 g 0.100 g Disodium hydrogen phosphate 12H ₂ O 0.755 g 0.755 g 0.755 g Sodium dihydrogen phosphate 2H ₂ O 0.061 g 0.061 g 0.061 g Glycerol 3.000 g 3.000 g 3.000 g Ethanol 3.651 g 4.251 g 3.711 g Sodium hydroxide 0.630 g 0.630 g 0.630 g Carbopol 974PNF 1.250 g 1.250 g 1.250 g Water 81.688 g 81.688 g 81.688 g Target agent. - in a continuous phase Capsaicin - 0.250 g 0.025 g Target agent. - in Transfersome Menthol 0.100 g 0.100 g 0.100 g total weight 100,000 g 100,000 g 100,000 g

Results.

The composition was tested on three individuals. The results are shown in the table below.

Table 26

Investigated product TP2 (PD-14-0073) Capsaicin Menthol In liposomes In Transfersome ™ membranes and liposomes CAPSAICIN: Onset of sensation Optimal Feeling Duration of sensation Expressiveness of sensation from 5 to 30 minutes from 15 to 60 minutes from 45 to 180 minutes Pleasant MENTHOL: Duration of sensation Intensity of sensation 15 to 30 minutes Sufficient

Conclusion / short description.

The preliminary results obtained allow us to assert that

A warming sensation from capsaicin can be felt:

in the Transfersome ™ - in the same phase as colloidal particles with a directed action on the joints;

in liposomes - in a phase other than colloidal particles with a directed effect on the joints

Example 6 Study of the use of a formulation containing caffeine in healthy volunteers to evaluate the improvement in the appearance of the skin around the eyes.

The present study tested the efficacy of a formulation containing caffeine and tocopherol in a continuous phase and three types of deformable colloidal particles: 1) Tethersomes to which palmitoyl ascorbate is attached, 2) Tethersomes to which palmitoyltripeptide-1 is attached, and 3) Tethersomes to which palmitoyl tetrapeptide is attached -7.

Ways.

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General protocol

Study design Simple blind Test item: Eye serum CBL-DERM-15-013 Duration of treatment: 4 weeks Number of subjects: 102 Subject type: Healthy men and women (of different nationalities) aged 40 to 70 years (in equal proportions, 33% in each age group with an interval of 10 years) of different nationalities with a variety of skin types (normal, combination, dry, oily, sensitive), who suffered from having two of the following characteristics: Puffiness around the eyes - swelling around the eyes Puffiness under the lower eyelids - "bags under the eyes" Dark circles around the eyes caused by a) aging, b) heredity, and c) excessive pigmentation (in people with dark skin color) (All three characteristics must be presented in equal proportions for the objectivity of the stated objectives). All subjects must have visible deep wrinkles, fine lines and crow's feet around the eyes Observations: Subjects were asked to apply the product according to the instructions for use. They were then asked to complete a self-perception questionnaire (SPQ) two weeks later and at the end of the study four weeks later. Method of treatment: Subjects were provided with test device samples and directions for use according to standard use. Research Center Princeton Consumer Research Harbor House 23 Chandlers Quay Maldon CM9 4LF United kingdom

Composition (CBL-DERM-15-013)

Organic phase - intermediate Quantity required per 100 g 1600ppm PAA agent final product (g) Soy Phosphatidylcholine (SPC) 4.12200 Ethanol 1.99660 Butylhydroxyanisole (BHA) 0.01200 Methyl 4-hydroxybenzoate 0.15000 Ethyl 4-hydroxybenzoate 0.15000 Benzyl alcohol 0.31500 Polysorbate 80 0.40800 Palmitoylcorbic acid 0.09600 +/- alpha-tocopherol 0.20000 Linalool 0.06000 Organic phase, total 7,50960 The aqueous phase is an intermediate agent 1600ppm PAA Sodium metabisulfite 0.03000 Citric acid monohydrate 0.04320 EDTA disodium 0.06000 Disodium hydrogen phosphate dodecahydrate 0.17280 Caffeine 0.05000 Water 27.13420 Water phase, total 27.49020 Tethersome Intermediate Agent with RAA, total 34.99980 Organic phase - intermediate agent ZOORT tetrapeptide Soy Phosphatidylcholine (SPC) 1.37400 Ethanol 0.74120 Butylhydroxyanisole (BHA) 0.00400 Methyl 4-hydroxybenzoate 0.05000 Ethyl 4-hydroxybenzoate 0.05000

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Benzyl alcohol Polysorbate 80 Palmitoyl peptide Linalool Organic phase, total 0.10500 0.15300 0.00600 0.02000 2.50320 The aqueous phase is an intermediate agent ZOORT tetrapeptide Sodium metabisulfite 0.01000 Citric acid monohydrate 0.01440 EDTA disodium 0.02000 Disodium hydrogen phosphate dodecahydrate 0.05760 Water 9.06140 Water phase, total 9.16340 Tethersome Intermediate Agent with tetrapeptide, total 11.66660 Organic phase - intermediate ZOORT tripeptide agent Soy Phosphatidylcholine (SPC) 1.37400 Ethanol 0.74120 Butylhydroxyanisole (VID) 0.00400 Methyl 4-hydroxybenzoate 0.05000 Ethyl 4-hydroxybenzoate 0.05000 Benzyl alcohol 0.10500 Polysorbate 80 0.15300 Palmitoyl peptide 0.00600 Linalool 0.02000 Organic phase, total 2.50320 The aqueous phase is an intermediate agent ZOORT tripeptide Sodium metabisulfite 0.01000 Citric acid monohydrate 0.01440 EDTA disodium 0.02000 Disodium hydrogen phosphate dodecahydrate 0.05760 Water 9.06140 Water phase, total 9.16340 Tethersome Intermediate Agent with tripeptide, total 11.66660 The total number of intermediate agents Sequessome and Tethersome 58.33300 Gel phase - final product Sodium hydroxide 0.16000 Carbopol 974Р NF 0.75000 Glycerol 3.00000 Citric acid monohydrate 0.05600 Disodium hydrogen phosphate dodecahydrate 0.24200 Water 37.45900 Gel phase, total 41.66700 Total 100,00000

General formula CBL-DERM-15-013

Ingredient (content as a percentage; g per 100 g) Skin around the eyes SPC (dry weight) 6,870 Polysorbate 80 0.714 Benzyl alcohol 0.525 Methyl 4-hydroxybenzoate 0.250 Ethyl 4-hydroxybenzoate 0.250 Butylhydroxyanisole 0.020 Linalool 0.100 Sodium metabisulfite 0.050 EDTA disodium 0.100 Disodium hydrogen phosphate 12H ₂ O 0.530 Citric acid monohydrate 0.128 Glycerol 3,000 Ethanol *** 3.479 Sodium hydroxide 0.160 Carbopol 974Р NF 0.750 Water Target agent. - attached 82,716 to Tethersomes

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Palmitoyltripeptide-1 0.006 Palmitoyltetrapeptide-7 0.006 Palmitoyl ascorbate 0.096 Target agent. - in a continuous phase Tocopherol 0.200 Caffeine 0.050 pH 5.5 *

* - the final pH is indicated approximately; confirmation is required.

Results.

Intra-group analysis (p <0.05) for the clinical assessment of the skin condition under the eyes shows a statistically significant reduction in deep wrinkles (15.69%), fine wrinkles (31.22%), crow's feet (21.47%), puffiness ( 38.07%), dark circles (26.01%) and bags under the eyes (38.94%) after 4 weeks of product use.

The product produced statistically effective results in a 4-week study on most metrics according to Clearcast's advertising guidelines. The product was preferred or effective on most scores:

After using the product, 96.08% of users agreed or completely agreed that the product reduced puffiness or swelling around the eyes.

After using the product, 96.08% of users agreed or completely agreed that the skin felt and looked less thin.

After using the product, 93.14% of users agreed or completely agreed that their skin felt more elastic.

After using the product, 96.08% of users agreed or completely agreed that the product reduced swelling and puffiness under the lower eyelids (bags under the eyes).

After using the product, 90.20% of users agreed or completely agreed that the product tightened saggy skin (reduced skin laxity and sagging).

After using the product, 92.16% of users agreed or completely agreed that the product reduced dark circles under the eyes.

After using the product, 95.10% of users agreed or completely agreed that their skin looked and felt firmer.

After using the product, 90.20% of users agreed or completely agreed that there was a reduction in fine lines (including crow's feet) around the eyes.

After using the product, 87.25% of users agreed or completely agreed that there was a reduction in deep wrinkles (including crow's feet) around the eyes.

After using the product, 93.14% of users found their skin tone to be smoother.

After using the product, 90.20% of users experienced a sharper eye contour look and feel.

After using the product, 90.20% of users experienced a smoother / tighter eye contour.

After using the product, 96.08% of users found their eyes rested / less tired.

After using the product, 97.06% of users felt that the skin of the eyes became more hydrated.

After using the product, 95.10% of users felt smoother looking skin.

After using the product, 99.02% of users agreed agree agree agree agree agree agree agree agree agree agree agree agree agree agree with s s s s s s s s s s s c s agree or agree or agree or agree or agree or agree or agree or completely completely completely completely completely completely that the product was soft and easily tolerated.

After using the product, 75.49% of users stated that they would buy this product instead of their commonly used product.

After using the product, 86.27% of users stated that they would recommend this product to a friend.

After using the product, 46.08% of users said they looked at least 5 years younger.

Example 7. Study of the use of a composition containing salicylate and tocopherol in healthy volunteers to evaluate the improvement in skin tone.

The present study examined the efficacy of a formulation containing tocopherol in a continuous phase and two types of colloidal particles: 1) the Tethersome, to which the tridecyl salicylate is attached, and 2) the Tethersome, to which the palmitoyl ascorbate and tocopheryl linoleate are attached.

Ways.

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General protocol

Study design: Simple blind Test item: Serum for improving skin tone CBL-DERM-15-014 Duration of treatment: 6 weeks Number of subjects: 110 Subject type: A study of the use of 110 healthy men (20%) and women (80%) between the ages of 20 and 70 (with equal proportions of age groups with an interval of 10 years; 20-year-olds, 30-year-olds, 40-year-olds, 50 years old, 60 years old, 70 years old); of different nationalities with different skin types who have suffered from one or two of the following six conditions: spots of melasma or chloasma, uneven skin tone, age, freckles or "liver" spots, lentigo, post-inflammatory overpigmentation or overpigmentation around the eyes (dark circles ). Observation: Subjects were asked to apply the product according to the instructions for use. They were asked to complete a self-perception questionnaire (SPQ) at the end of weeks 3 and 6. Method of treatment: Subjects were provided with test device samples and directions for use in accordance with standard use. Research Center Princeton Consumer Research Harbor House 23 Chandlers Quay Maldon CM9 4LF United kingdom

Composition (CBL-DERM-15-014)

The organic phase is an intermediate agent Quantity required per 100 g with tridecyl salicylate final product (g) Soy Phosphatidylcholine (SPC) 3.43500 Ethanol 1.67550 Butylhydroxyanisole (BHA) 0.01000 Methyl 4-hydroxybenzoate 0.12500 Ethyl 4-hydroxybenzoate 0.12500 Benzyl alcohol 0.26250 Polysorbate 80 0.42500 Tridecyl salicylate 0.10000 +/- alpha-tocopherol 0.05000 Linalool 0.05000 Organic phase, total 6,25800 The aqueous phase is an intermediate agent with tridecyl salicylate Citric acid monohydrate 0.03600 EDTA disodium 0.05000 Sodium metabisulfite 0.02500 Disodium hydrogen phosphate dodecahydrate 0.14400 Water 22.65350 Water phase, total 22.90850 Tethersome Intermediate Agent with tridecyl salicylate, total 29.16650 Organic phase - intermediate with PAA / tocopheryl linoleate Soy Phosphatidylcholine (SPC) 3.43500 Ethanol 1.57950 Butylhydroxyanisole (BHA) 0.01000 Methyl 4-hydroxybenzoate 0.12500 Ethyl 4-hydroxybenzoate 0.12500 Benzyl alcohol 0.26250 Polysorbate 80 0.42500 Palmitoylcorbic acid 0.09600 T okoferill inoleate 0.10000

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+/- alpha-tocopherol 0.05000 Linalool 0.05000 Organic phase, total 6,25800 The aqueous phase is an intermediate with PAA / tocopheryl linoleate Citric acid monohydrate 0.03600 EDTA disodium 0.05000 Sodium metabisulfite 0.02500 Disodium hydrogen phosphate dodecahydrate 0.14400 Water 22.65350 Water phase, total 22.90850 Tethersome Intermediate with PAA / Tocopheryl Linoleate, Total 29.16650 Total number of intermediate agents Sequessome and Tethersome 58.33300 Gel phase - final product Sodium hydroxide 0.16000 Carbopol 974PNF 0.75000 Glycerol 3.00000 Citric acid monohydrate 0.05600 Disodium orthohydrogen phosphate dodecahydrate 0.24200 Water 37.45900 Gel phase, total 41.66700 Total 100,00000

General formula CBL-DERM-15-014

Ingredient (in percent; g per 100 g) Uneven skin tone ** SPC (dry weight) 6,870 Polysorbate 80 0.850 Benzyl alcohol 0.525 Methyl 4-hydroxybenzoate 0.250 Ethyl 4-hydroxybenzoate 0.250 Butylhydroxyanisole 0.020 Linalool 0.100 Sodium metabisulfite 0.050 EDTA disodium 0.100 Disodium hydrogen phosphate 12H2O 0.530 Citric acid monohydrate 0.128 Glycerol 3,000 Ethanol *** 3.255 Sodium hydroxide 0.160 Carbopol 974Р NF 0.750 Water Target agent. - attached 82,766th to Tethersome Palmitoyl ascorbate 0.096 Tocopheryllinoleate 0.100 Tridecyl salicylate Target agent. - in continuous Tocopherol 0.100 1st phase | 0.100 pH | 5.5 * ^**

* - the final pH is indicated approximately; confirmation is required.

** - The source of SPC (dry matter) for uneven skin tone is the lipoid phospholipon 90K (P90K). The amount of P90K and ethanol to be added is calculated accordingly.

Results.

The product produced statistically effective results in a 6-week study on most metrics according to Clearcast's advertising guidelines. The product was preferred or effective on most scores:

After using the product, 100% of users agreed or strongly agreed that the product reduced fine and deep wrinkles.

After using the product, 100% of users agreed or strongly agreed that their skin looked significantly smoother.

After using the product, 100% of users agreed or strongly agreed that their skin looked significantly healthier.

After using the product, 96.36% of users agreed or strongly agreed that their skin felt more elastic.

- 53 038613

After using the product, 99.09% of users agreed or strongly agreed that their face looked younger.

After using the product, 99.09% of users agreed or strongly agreed that their complexion had noticeably improved.

After using the product, 100% of users agreed or strongly agreed that their complexion became noticeably brighter.

After using the product, 100% of users agreed or completely agreed that their face looked significantly healthier.

After using the product, 98.18% of users agreed or strongly agreed that their skin tone was significantly smoother.

After using the product, 96.36% of users agreed or strongly agreed that the number of areas of excess pigmentation / age spots was significantly reduced.

After using the product, 97.27% of users agreed or strongly agreed that the size of the areas of excess pigmentation / age spots was significantly reduced.

After using the product, 99.09% of users agreed or strongly agreed that the areas of excess pigmentation / age spots were significantly lighter.

After using the product, 20.00% of users agreed or strongly agreed that the areas of excess pigmentation / age spots had completely disappeared.

After using the product, 100% of users agreed or strongly agreed that the dark circles around the eyes became significantly lighter.

After using the product, 95.45% of users agreed or strongly agreed that this was the most effective anti-pigmentation treatment they have ever used.

After using the product, 92.73% of users stated that they would buy this product instead of their usual product.

After using the product, 100% of users claimed that they would recommend this product to a friend.

In terms of packaging design / promotional promises, any results with maximum indices of 3 and 4 over 80% are extremely favorable.

Claims (19)

CLAIM 1. A composition containing a first colloidal dispersion and a second colloidal dispersion, where each colloidal dispersion contains deformable colloidal particles containing a surfactant, and wherein one or more of said deformable colloidal particles in the first colloidal dispersion contain a modified component containing the first target agent (CA), wherein said modified component is a lipid or surfactant associated with said CA so that CA is completely outside the particle membrane, and wherein said first CA is zinc. 2. The composition according to claim 1, characterized in that said deformable colloidal particles additionally contain a phospholipid. 3. The composition according to claim 1 or 2, characterized in that one or more of said deformable colloidal particles in the second colloidal dispersion contain a modified component containing a second CA, wherein the first CA and the second CA are different, and said second CA is selected from a group consisting of an element, an ion, an inorganic salt, a small molecule, an amino acid, a peptide, a protein, a carbohydrate, a lipid, a micronutrient, a macromolecule, or a macrocyclic molecule. 4. The composition according to claim 3, characterized in that one or more of said deformable colloidal particles in the first colloidal dispersion and / or one or more deformable colloidal particles in the second colloidal dispersion contain one or more additional CA, where each CA is different, and said second and / or additional CA is selected from the group consisting of ascorbate, tetrapeptide, tripeptide, salicylic acid, vitamin D, tocopherol and menthol. 5. Composition according to claim 1 or 2, characterized in that said composition contains chlorhexidine, salicylic acid, capsaicin, caffeine or tocopherol. 6. Composition according to claim 5, characterized in that chlorhexidine, salicylic acid, capsaicin, caffeine or tocopherol is not (a) bound to said deformable colloidal particles. 7. Use of a composition according to claim 1 or 2 for the treatment or prevention of a disease. 8. Use of a composition according to claim 1 or 2 for the treatment or prevention of acne. 9. Use of a composition according to claim 1 or 2 for treating or preventing dry skin, pruritus, skin redness, skin irritation, flaky skin, skin aging, skin thinning, uneven skin tone, skin around the eyes, photoaging of skin or dermatitis. - 54 038613 10. Use of a composition according to claim 1 or 2 for skin care and / or cosmetics. 11. Use of a composition according to claim 1 or 2 for the cosmetic treatment of a subject. 12. A method of cosmetically improving the appearance of a subject, comprising topically applying a composition according to claim 1 or 2 to the skin of the subject. 13. A method of obtaining a composition according to claim 1 or 2, comprising the following stages: a) obtaining a first colloidal dispersion by mixing an organic phase containing alcohol-soluble components of said first colloidal dispersion and an aqueous phase containing water-soluble components of said first colloidal dispersion; b) obtaining a second colloidal dispersion by mixing an organic phase containing alcohol-soluble components of said second colloidal dispersion and an aqueous phase containing water-soluble components of said second colloidal dispersion; and c) obtaining a gel phase and dispersing said first and second colloidal dispersions in said gel phase. 14. A method of treating a disease in a subject, comprising topically applying a composition comprising a first colloidal dispersion and a second colloidal dispersion, where each colloidal dispersion contains deformable colloidal particles containing a surfactant, and where one or more of said deformable colloidal particles in the first colloidal dispersion contains a modified component containing a first target agent (CA), wherein said modified component is a lipid or surfactant associated with said CA, so that CA is completely outside the particle membrane, and wherein said first CA is are zinc. 15. The method according to claim 14, wherein said deformable colloidal particles further comprise a phospholipid. 16. A method for delivering CA to or through the skin of a patient, comprising topically applying to the patient's skin a composition according to claim 1 or 2 in an amount sufficient to pass through the skin to deliver CA. 17. A set containing one or more cells, where at least one cell contains a composition containing a first colloidal dispersion and a second colloidal dispersion, where each colloidal dispersion contains deformable colloidal particles containing a surfactant, and where one or more deformable colloidal particles in the first colloidal dispersion contains a modified component containing the first target agent (CA), wherein said modified component is a lipid or surfactant associated with said CA, so that when said CA is outside of said particle, CA is completely outside the membrane of the particle, and the specified kit contains instructions for administering the composition to a subject in need thereof. 18. The kit according to claim 17, wherein said deformable colloidal particles further comprise a phospholipid. 19. A device for transdermal drug release comprising a support layer and a layer containing a composition according to claim 1 or 2.